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COMPOUND SUMMARY
Acetaminophen
PubChem CID: 1983
Structure:
2D 3D Crystal
Chemical Safety:
Irritant
acetaminophen
Paracetamol
4-Acetamidophenol
Synonyms: 103-90-2
N-(4-Hydroxyphenyl)acetamide
More...
Modify: Create:
Dates:
2020-10-03 2004-09-16
Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities. Although the exact mechanism through which acetaminophen exert its effects has yet to be fully
determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA) and substance P,
resulting in elevation of the pain threshold. The antipyretic activity may result from inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and
prostaglandin-mediated effects on the heat-regulating center in the anterior hypothalamus.
Acetaminophen is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. Harmless at low doses, acetaminophen has direct hepatotoxic
potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. Even in therapeutic doses, acetaminophen can cause transient serum
aminotransferase elevations.
LiverTox
Acetaminophen, also known as paracetamol or apap, belongs to the class of organic compounds known as 1-hydroxy-2-unsubstituted benzenoids. These are phenols that are
unsubstituted at the 2-position. Acetaminophen is a drug which is used for temporary relief of fever, minor aches, and pains. Acetaminophen exists as a solid, slightly soluble (in water),
and a very weakly acidic compound (based on its pKa). Acetaminophen has been found throughout all human tissues, and has also been detected in most biofluids, including saliva, feces,
blood, and cerebrospinal fluid. Within the cell, acetaminophen is primarily located in the cytoplasm. Acetaminophen participates in a number of enzymatic reactions. In particular,
Acetaminophen can be converted into NAPQI through the action of the enzymes cytochrome P450 2E1, cytochrome P450 1A2, cytochrome P450 2D6, cytochrome P450 3A4, and
cytochrome P450 2A6. In addition, Acetaminophen and uridine diphosphate glucuronic acid can be converted into acetaminophen glucuronide and uridine 5'-diphosphate through the
action of the enzymes UDP-glucuronosyltransferase 1-9, UDP-glucuronosyltransferase 2B15, UDP-glucuronosyltransferase 1-1, and UDP-glucuronosyltransferase 1-6. In humans,
acetaminophen is involved in the acetaminophen metabolism pathway and the acetaminophen action pathway. Acetaminophen has a bitter taste. Acetaminophen is a potentially toxic
compound.
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 1/69
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1 Structures
1.1 2D Structure
Chemical Structure
Depiction
PubChem
1.2 3D Conformer
Interactive Chemical
Structure Model
Sticks
Wire-Frame
Space-Filling
Show Hydrogens
Animate
PubChem
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N-(4-hydroxyphenyl)acetamide
Computed by LexiChem 2.6.6 (PubChem release 2019.06.18)
PubChem
2.1.2 InChI
InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10)
Computed by InChI 1.0.5 (PubChem release 2019.06.18)
PubChem
RZVAJINKPMORJF-UHFFFAOYSA-N
Computed by InChI 1.0.5 (PubChem release 2019.06.18)
PubChem
CC(=O)NC1=CC=C(C=C1)O
Computed by OEChem 2.1.5 (PubChem release 2019.06.18)
PubChem
HOC6H4NHCOCH3
C8H9NO2
Wikipedia; PubChem
2.3.1 CAS
103-90-2
CAMEO Chemicals; ChemIDplus; DrugBank; DTP/NCI; EPA Chemicals under the TSCA; EPA DSSTox; European Chemicals Agency (ECHA); Hazardous Substances Data Bank (HSDB); Human Metabolome Database (HMD
ChemIDplus
203-157-5
1330
755853
DTP/NCI
109028
DTP/NCI
3991
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DTP/NCI
AE4200000
2.3.7 UNII
362O9ITL9D
9278
DTXSID2020006
EPA DSSTox
2.3.10 Wikipedia
Acetaminophen
Wikipedia
2.4 Synonyms
Acamol N-(4-Hydroxyphenyl)acetanilide
Acephen N-Acetyl-p-aminophenol
Acetaco p-Acetamidophenol
Acetamidophenol p-Hydroxyacetanilide
Acetaminophen Panadol
Acetominophen Paracetamol
Algotropyl Tylenol
Anacin 3
Anacin-3
Anacin3
APAP
Datril
Hydroxyacetanilide
MeSH
acetaminophen p-Acetamidophenol Gelocatil Homoolan Eneril Ortensan Biocetamol Minoset Temlo Grippostad
Paracetamol Algotropyl Injectapap Lestemp Fendon Paldesic Dafalgan Napafen 4-(Acetylamino)phenol Gynospasmine
4-Acetamidophenol Lonarid Liquagesic Paracet Hedex Banesin Dolgesic Neodol Ben-u-ron Medocodene
103-90-2 Naprinol Pyrinazine Tabalgin Lyteca Captin Elixodyne Nobedon Dial-A-Gesic Paedialgon
N-(4-Hydroxyphenyl)acetamide Acamol Servigesic Tralgon Pacemo Disprol Febrectal Pacemol Anacin-3 Paracetamolum
Tylenol Acenol Alvedon Tussapap Panets Enelfa Tempanal Panodil Calmanticold Paracetanol
APAP Anelix Anaflon Valadol Parmol Neopap Vermidon Parapan Codoliprane Parakapton
Panadol Multin Apamide Valgesic Tapar Salzone Abenol Pedric Demogripal Pediapirin
Acetaminofen p-Acetaminophenol Dymadon Alpiny Tempra Exdol Apacet Phendon Dolegrippin Phenipirin
Datril Abensanil Febridol Amadil Paracetamolo p-Acetylaminophenol Apadon Rounox Doloreduct Phogoglandin
N-Acetyl-p-aminophenol Acetagesic Febrilix Anhiba Doliprane Febro-Gesic Cetadol Suppap Dristancito Predualito
p-Hydroxyacetanilide Acetalgin Febrolin Calpol Dolprone NEBS Fensum Korum Duracetamol Sanicopyrine
4'-Hydroxyacetanilide Clixodyne Finimal Dirox Momentum Acetamide, N-(4-hydroxyphenyl)- Janupap Pinex Eu-Med Scentalgyl
PubChem
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Molecular Weight 151.16 g/mol Computed by PubChem 2.1 (PubChem release 2019.06.18)
Hydrogen Bond Donor Count 2 Computed by Cactvs 3.4.6.11 (PubChem release 2019.06.18)
Hydrogen Bond Acceptor Count 2 Computed by Cactvs 3.4.6.11 (PubChem release 2019.06.18)
Exact Mass 151.063329 g/mol Computed by PubChem 2.1 (PubChem release 2019.06.18)
Monoisotopic Mass 151.063329 g/mol Computed by PubChem 2.1 (PubChem release 2019.06.18)
Topological Polar Surface Area 49.3 Ų Computed by Cactvs 3.4.6.11 (PubChem release 2019.06.18)
PubChem
4-hydroxyacetanilide is an odorless white crystalline solid. Bitter taste. pH (saturated aqueous solution) about 6. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
CAMEO Chemicals
Solid
3.2.2 Color/Form
3.2.3 Odor
Odorless
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11
3.2.4 Taste
>500
http://www.inchem.org/documents/icsc/icsc/eics1330.htm
DrugBank
>500 °C
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CAMEO Chemicals
170
MSDS
DrugBank
170.0 °C
EPA DSSTox
168 °C
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 94th Edition. CRC Press LLC, Boca Raton: FL 2013-2014, p. 3-314
170°C
169-170 °C
3.2.7 Solubility
CAMEO Chemicals
very slightly soluble in cold water but greater solubility in hot water
http://www.inchem.org/documents/pims/pharm/pim396.htm
DrugBank
0.09 M
YALKOWSKY,SH & HE,Y (2003)
EPA DSSTox
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
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
14 mg/mL at 25 °C
>22.7 [ug/mL]
3.2.8 Density
CAMEO Chemicals
1.293 g/cu cm at 21 °C
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 94th Edition. CRC Press LLC, Boca Raton: FL 2013-2014, p. 3-314
1.3 g/cm³
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3.2.9 Vapor Density
6.29X10-5 mm Hg at 25 °C
Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989.
3.2.11 LogP
0.91
http://www.t3db.ca/toxins/T3D2571
DrugBank
0.46 (LogP)
SANGSTER (1994)
EPA DSSTox
0.46
SANGSTER (1994)
0.49
3.2.12 LogS
-1.6
http://www.t3db.ca/toxins/T3D2571
DrugBank
540 °C
3.2.15 pH
3.2.16 pKa
DrugBank
pKa = 9.38
Dastmalchi S et al; J Sch Pharm, Med Sci Univ Tehran 4: 7-14 (1995)
132.2 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
https://www.sciencedirect.com/science/article/pii/S0021967318301894
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CCSbase
129.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
https://pubs.acs.org/doi/abs/10.1021/acs.analchem.7b01709
CCSbase
131.43 Ų [M-H]-
130.56 Ų [M+H]+
S61 | UJICCSLIB | Collision Cross Section (CCS) Library from UJI | DOI:10.5281/zenodo.3549476
132.7 Ų [M-H]-
139.3 Ų [M+H]+
S50 | CCSCOMPEND | The Unified Collision Cross Section (CCS) Compendium | DOI:10.5281/zenodo.2658162
Standard non-polar 1668, 1636, 1631, 1631, 1632, 1643, 1650, 1664, 1678, 1675.7, 1694.6, 1652.3, 1631, 1636, 1687
MP: 169-170.5 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
SpringerMaterials
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4 Spectral Information
NMRShiftDB
Thumbnail
SpectraBase
Thumbnail
SpectraBase
Copyright Copyright © 1980, 1981-2018 Bio-Rad Laboratories, Inc. All Rights Reserved.
Thumbnail
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SpectraBase
Copyright Copyright © 2016 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
Thumbnail
SpectraBase
Copyright Copyright © 2016-2018 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
Thumbnail
SpectraBase
Copyright Copyright © 2016-2018 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
Thumbnail
SpectraBase
Source of Spectrum Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright Copyright © 2012-2018 Bio-Rad Laboratories, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
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Thumbnail
SpectraBase
Source of Spectrum Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright Copyright © 2012-2018 Bio-Rad Laboratories, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
Thumbnail
SpectraBase
4.3.1 GC-MS
MoNA ID MoNA002546
MS Category Experimental
MS Type GC-MS
MS Level MS1
Splash splash10-0a4i-1290000000-845dca4dc2d32ce68b7e
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4.3.2 MS-MS
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Showing 2 of 4 View More
MS-MS Spectrum 1732 - Acetaminophen (HMDB0001859) MS-MS Spectrum 435684 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 1733 - Acetaminophen (HMDB0001859) MS-MS Spectrum 435685 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 1734 - Acetaminophen (HMDB0001859) MS-MS Spectrum 435686 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 5497 - Acetaminophen (HMDB0001859) MS-MS Spectrum 435687 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 5498 - Acetaminophen (HMDB0001859) MS-MS Spectrum 435688 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 5499 - Acetaminophen (HMDB0001859) MS-MS Spectrum 435689 - Acetaminophen (HMDB0001859)
MS-MS MS-MS Spectrum 435677 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 435678 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 435679 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 435680 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 435681 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 435682 - Acetaminophen (HMDB0001859)
MS-MS Spectrum 435683 - Acetaminophen (HMDB0001859)
Collision Energy 0
Total Peaks 5
Thumbnail
4.3.3 LC-MS
MoNA ID MoNA010059
MS Category Experimental
MS Type LC-MS
MS Level MS1
Splash splash10-0udi-0900000000-82534c59fd3b2cbd6088
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MassBank of North America (MoNA)
MoNA ID MoNA010060
MS Category Experimental
MS Type LC-MS
MS Level MS2
Splash splash10-0ik9-1900000000-7d3d223a17409104bcaa
Thumbnail
4.3.4 EI-MS
4.3.5 Other MS
Other MS Intense mass spectral peaks: 80 m/z, 109 m/z, 151 m/z
MoNA ID MoNA010874
MS Category Experimental
MS Level MS2
Splash splash10-0w29-0900000000-3b1d1d0e4e4eaad47294
Thumbnail
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4.4 UV Spectra
UV max (ethanol): 250 nm (epsilon 13800)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
4.5 IR Spectra
IR Spectra IR: 5420 (Coblentz Society spectral collection)
Copyright Copyright © 1980, 1981-2018 Bio-Rad Laboratories, Inc. All Rights Reserved.
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SpectraBase
Copyright Copyright © 1980, 1981-2018 Bio-Rad Laboratories, Inc. All Rights Reserved.
Thumbnail
SpectraBase
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SpectraBase
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SpectraBase
Technique FT-Raman
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SpectraBase
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5 Related Records
PubChem
PubChem
5.3 Substances
PubChem
PubChem
Taxonomy 13 Records
OMIM 58 Records
PubChem
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NCBI
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6 Chemical Vendors
PubChem
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In general, acetaminophen is used for the treatment of mild to moderate pain and reduction of fever.[F4124] It is available over the counter in various forms, the most common being oral
forms. Acetaminophen _injection_ is indicated for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction
of fever.[Label] Because of its low risk of causing allergic reactions, this drug can be administered in patients who are intolerant to salicylates and those with allergic tendencies, including
bronchial asthmatics.[F4124] Specific dosing guidelines should be followed when administering acetaminophen to children.[L5780]
DrugBank
FDA Label
DrugBank
LiverTox
LiverTox
FDA Drugs
NDC Code(s) 0023-6002-01, 0023-6021-01, 0023-6021-05, 0023-6022-01, 0023-6022-05, 0031-2249-04, 0031-8721-02, 0031-8721-20, 0031-8744-10, 0031-8750-12 ... total 10153.
7-Eleven; 7T Pharma LLC; A P J Laboratories Limited; A&Z Holistic Products, Inc.; A-S Medication Solutions; AAA Pharmaceutical, Inc.; AAFES/Your Military Exchanges; ACTIPHARMA,
Packagers
INC; ADVANCED FIRST AID, INC.; AGILE PHARMACHEM ... total 686.
DailyMed
NDC Code(s) 0023-6002-01, 0023-6021-01, 0023-6021-05, 0023-6022-01, 0023-6022-05, 0031-2249-04, 0031-8721-02, 0031-8721-20, 0031-8744-10, 0031-8750-12 ... total 10153.
7-Eleven; 7T Pharma LLC; A P J Laboratories Limited; A&Z Holistic Products, Inc.; A-S Medication Solutions; AAA Pharmaceutical, Inc.; AAFES/Your Military Exchanges; ACTIPHARMA,
Packagers
INC; ADVANCED FIRST AID, INC.; AGILE PHARMACHEM ... total 686.
DailyMed
7.6.1 ClinicalTrials.gov
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ClinicalTrials.gov
Narcotic Yes
Decision Type W: decision granting a waiver in all age groups for all conditions or indications
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European Medicines Agency (EMA)
Decision Type W: decision granting a waiver in all age groups for all conditions or indications
Ofirmev (acetaminophen) injection is indicated for the management of mild to moderate pain the management of moderate to severe pain with adjunctive opioid analgesics the reduction of
fever. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
Acetaminophen is used to provide temporary analgesia in the treatment of mild to moderate pain. Acetaminophen also is used in fixed combination with other agents (e.g., chlorpheniramine,
dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, pseudoephedrine) for short-term relief of minor aches and pain, headache, and/or other symptoms (e.g.,
rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, nasal congestion, cough) associated with seasonal allergic rhinitis (e.g., hay fever), other upper respiratory allergies,
or the common cold.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
Acetaminophen has been used in the treatment of pain in various combinations with aspirin, caffeine, opiates, and/or other agents. Acetaminophen ... in combination with oral doses of an
opiate (e.g., codeine, oxycodone) produces greater analgesic effect than that produced by either acetaminophen or higher doses of the opiate alone.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
Acetaminophen in fixed combination with aspirin and caffeine ... is used for the temporary relief of mild to moderate pain associated with migraine headache. Some experts state that this
combination also may be used for the treatment of severe migraine headache if previous attacks have responded to similar nonopiate analgesics or nonsteroidal anti-inflammatory agents
(NSAIAs).
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
Acetaminophen in fixed combination with isometheptene and dichloralphenazone also is used for symptomatic relief of vascular headaches.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
Acetaminophen is used in the symptomatic treatment of pain associated with osteoarthritis and is considered an initial drug of choice for pain management in osteoarthritis patients.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
If an antipyretic is considered necessary in children or teenagers with known or suspected varicella, influenza-like illness, or other viral illness, use of acetaminophen (not aspirin) is
recommended because use of salicylates in these pediatric patients may be associated with an increased risk of developing Reye's syndrome.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2207
Acetaminophen is used frequently to lower body temperature in febrile patients in whom fever may be deleterious or in whom considerable relief is obtained when fever is lowered.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
Acetaminophen in fixed combination with isometheptene and dichloralphenazone is used for symptomatic relief of tension headache.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
MEDICATION (VET): In arthritic & inflammatory syndromes to relieve pain & reduce fever.
Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974., p. 1
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should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin
reactions.
US FDA; FDA Drug Safety Communication: FDA Warns of Rare but Serious Skin Reactions with the Pain Reliever/Fever Reducer Acetaminophen (8/1/2013). Available from, as of March 6, 2014:
http://www.fda.gov/drugs/drugsafety/ucm363041.htm
FDA is recommending health care professionals discontinue prescribing and dispensing prescription combination drug products that contain more than 325 milligrams (mg) of
acetaminophen1 per tablet, capsule, or other dosage unit. There are no available data to show that taking more than 325 mg of acetaminophen per dosage unit provides additional benefit that
outweighs the added risks for liver injury. Further, limiting the amount of acetaminophen per dosage unit will reduce the risk of severe liver injury from inadvertent acetaminophen overdose,
which can lead to liver failure, liver transplant, and death.
US FDA; FDA Drug Safety and Availability: FDA recommends health care professionals discontinue prescribing and dispensing prescription combination drug products with more than 325 mg of acetaminophen to protect
consumers (1/14/2014). Available from, as of March 9, 2014: http://www.fda.gov/Drugs/DrugSafety/ucm381644.htm
/BOXED WARNING/ WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY. Take care when prescribing, preparing, and administering Ofirmev Injection to avoid dosing errors which
could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (mL) is not confused; the dosing is based on weight for patients
under 50 kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. Ofirmev contains acetaminophen.
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of
acetaminophen at doses that exceed the maximum daily limits, and often involve more than one acetaminophen-containing product.
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia
(e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance = 30 mL/min).
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
For more Drug Warnings (Complete) data for ACETAMINOPHEN (23 total), please visit the HSDB record page.
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bitter
FooDB
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9 Agrochemical Information
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10.1 Pharmacology
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.[F4124] Acetaminophen does
not disrupt hemostasis and does not have inhibitory activities against platelet aggregation.[Label,F4124] Allergic reactions are rare occurrences following acetaminophen use.[F4124]
DrugBank
Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities. Although the exact mechanism through which acetaminophen exert its effects has yet to be fully
determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA) and substance P,
resulting in elevation of the pain threshold. The antipyretic activity may result from inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and prostaglandin-
mediated effects on the heat-regulating center in the anterior hypothalamus.
Drugs that are used to reduce body temperature in fever. (See all compounds classified as Antipyretics.)
MeSH
Analgesics, Non-Narcotic
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. (See all
compounds classified as Analgesics, Non-Narcotic.)
MeSH
N02BE - Anilides
N02BE01 - Paracetamol
Acetaminophen has 88% oral bioavailability and reaches its highest plasma concentration 90 minutes after ingestion.[A35815] 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).[F4124] 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.[Label]
DrugBank
Route of Elimination
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.[F4124]
DrugBank
Volume of Distribution
Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells.[A176357] Acetaminophen appears to be widely distributed throughout most body tissues except in
fat.[Label]
DrugBank
Clearance
Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose.[Label] Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).[Label]
DrugBank
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.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
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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.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
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.
Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 11
Acetaminophen is rapidly and uniformly distributed into most body tissues. About 25% of acetaminophen in blood is bound to plasma proteins.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
For more Absorption, Distribution and Excretion (Complete) data for ACETAMINOPHEN (11 total), please visit the HSDB record page.
10.5 Metabolism/Metabolites
Acetaminophen is the major metabolite of _phenacetin_ and _acetanilid_.[F4124] 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.[Label] 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.[A35814]
DrugBank
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.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
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.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
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/
Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. A-10
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.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 704
The liver biotransforms 90% of accetaminophen by conversion in sulfate or glucuronide. The sulfate pathway predominates in children under 12 years of age, whereas adults primarily use the
glucuronide pathway. Unchanged renal excretion accounts for less than 5% of the elimination. A small portion of the therapeutic dose (about 5% with an upper limit of 15% to 20%) is
metabolized by the p450 mixed-function oxidase pathway to a reactive intermediary. In the presence of adequate glutathione stores, this intermediary is detoxified to mercapturic acid
conjugates and cysteine. Formation of oxidative metabolities and renal excretion appear to follow first-order kinetics (ie, elimination rate is concentration dependent); the conjugation of
sulfate and glucuronide metabolites follow Michaelis-Menten kinetic (combined zero- and first-order).
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. 157
Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: Conjugation with glucuronide, conjugation with sulfate, and oxidation
via the cytochrome P450 enzyme pathway, primarily CYP2E1, to form a reactive intermediate metabolite (N-acetyl-p-benzoquinone imine or NAPQI). With therapeutic doses, NAPQI
undergoes rapid conjugation with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates.
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15mg/kg dose of liquid versus solid
preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no
difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition
was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm.
PMID:23436315
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383763
Ganetsky M et al; J Clin Pharmacol. 53 (4): 413-20 (2013)
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DrugBank
The elimination half life is 1-3 hours after a therapeutic dose but may be greater than 12 hours after an overdose.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69
DrugBank
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.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2211
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.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2211
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.
PMID:20720158
Nassini R et al; FASEB J 24 (12): 4904-16 (2010)
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.
PMID:24501102
Karadas S et al; Hum Exp Toxicol 33 (11): 1134-40 (2014)
The mechanism by which acetaminophen (APAP) causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the
relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD) compared to male C57BL/6 mice in order to identify the cause(s) of sensitivity. Furthermore, /the researchers/
use mice that are either heterozygous (HZ) or null (KO) for glutamate cysteine ligase modifier subunit (Gclm), in order to titrate the toxicity relative to wild-type (WT) mice. Gclm is important
for efficient de novo synthesis of glutathione (GSH). APAP (300 mg/kg, ip) or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 hr. Male mice showed marked
elevation in serum alanine aminotransferase by 6 hr. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to
male mice. Genotype-matched male and female mice showed comparable APAP-protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice
showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but
rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of
mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.
PMID:24563856
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926121
Mohar I et al; Redox Biol 2: 377-87 (2014)
One of the products of normal metabolism of acetaminophen by cytochrome p450 mixed-function oxidase enzymes is highly toxic; normally this reactive metabolite (NAPQI) is detoxified
rapidly by glutathione in liver cells. however, in an overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts directly with hepatic macromolecules, causing liver
injury.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69
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Acetaminophen (APAP) overdose causes liver injury in humans and mice. DNA fragmentation is a hallmark of APAP-induced cell death, and nuclear translocation of apoptosis-inducing factor
(AIF) correlates with DNA fragmentation after APAP overdose. To test the hypothesis that AIF may be a critical mediator of APAP-induced cell death, fasted male AIF-deficient Harlequin (Hq)
mice and respective wild-type (WT) animals were treated with 200 mg/kg APAP. At 6 h after APAP, WT animals developed severe liver injury as indicated by the increase in plasma alanine
aminotransferase (ALT) activities (8600 + or - 1870 U/l) and 61 + or - 8% necrosis. This injury was accompanied by massive DNA strand breaks in centrilobular hepatocytes (terminal
deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay) and release of DNA fragments into the cytosol (anti-histone ELISA). In addition, there was formation of reactive
oxygen (increase in liver glutathione disulfide (GSSG) levels and mitochondrial protein carbonyls) and peroxynitrite (nitrotyrosine (NT) staining) together with mitochondrial translocation of
activated c-jun-N-terminal kinase (P-JNK) and release of AIF from the mitochondria. In contrast, Hq mice had significantly less liver injury (ALT: 330 + or - 130 U/l; necrosis: 4 + or - 2%), minimal
nuclear DNA damage, and drastically reduced oxidant stress (based on all parameters) at 6 h. WT and Hq mice had the same baseline levels of cyp2E1 and of glutathione. The initial depletion
of glutathione (20 min after APAP) was the same in both groups suggesting that there was no relevant difference in metabolic activation of APAP. Thus, AIF has a critical function in APAP
hepatotoxicity by facilitating generation of reactive oxygen in mitochondria and, after nuclear translocation, AIF can be involved in DNA fragmentation.
PMID:21572097
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155087
Bajt ML et al; Toxicol Sci 122 (2): 598-605 (2011)
Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. In the last four decades much progress has been made in our understanding of APAP-induced
liver injury through rodent studies. However, some differences exist in the time course of injury between rodents and humans. To study the mechanism of APAP hepatotoxicity in humans, a
human-relevant in vitro system is needed. Here we present evidence that the cell line HepaRG is a useful human model for the study of APAP-induced liver injury. Exposure of HepaRG cells to
APAP at several concentrations resulted in glutathione depletion, APAP-protein adduct formation, mitochondrial oxidant stress and peroxynitrite formation, mitochondrial dysfunction
(assessed by JC-1 fluorescence), and lactate dehydrogenase (LDH) release. Importantly, the time course of LDH release resembled the increase in plasma aminotransferase activity seen in
humans following APAP overdose. Based on propidium iodide uptake and cell morphology, the majority of the injury occurred within clusters of hepatocyte-like cells. The progression of injury
in these cells involved mitochondrial reactive oxygen and reactive nitrogen formation. APAP did not increase caspase activity above untreated control values and a pancaspase inhibitor did not
protect against APAP-induced cell injury. These data suggest that key mechanistic features of APAP-induced cell death are the same in human HepaRG cells, rodent in vivo models, and primary
cultured mouse hepatocytes. Thus, HepaRG cells are a useful model to study mechanisms of APAP hepatotoxicity in humans.
PMID:21319200
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073317
McGill MR et al; Hepatology 53 (3): 974-82 (2011)
Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in many countries. The mechanism of cell death is initiated by formation of a reactive metabolite that
binds to mitochondrial proteins and promotes mitochondrial dysfunction and oxidant stress. Manganese superoxide dismutase (SOD2) is a critical defense enzyme located in the mitochondrial
matrix. The objective of this investigation was to evaluate the functional consequences of partial SOD2-deficiency (SOD2+/-) on intracellular signaling mechanisms of necrotic cell death after
APAP overdose. Treatment of C57Bl/6J wild type animals with 200mg/kg APAP resulted in liver injury as indicated by elevated plasma alanine aminotransferase activities (2870 + or - 180U/L)
and centrilobular necrosis at 6h. In addition, increased tissue glutathione disulfide (GSSG) levels and GSSG-to-GSH ratios, delayed mitochondrial GSH recovery, and increased mitochondrial
protein carbonyls and nitrotyrosine protein adducts indicated mitochondrial oxidant stress. In addition, nuclear DNA fragmentation (TUNEL assay) correlated with translocation of Bax to the
mitochondria and release of apoptosis-inducing factor (AIF). Furthermore, activation of c-jun-N-terminal kinase (JNK) was documented by the mitochondrial translocation of phospho-JNK.
SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA
fragmentation and more prolonged JNK activation. ... The impaired defense against mitochondrial superoxide formation in SOD2+/- mice prolongs JNK activation after APAP overdose and
consequently further enhances the mitochondrial oxidant stress leading to exaggerated mitochondrial dysfunction, release of intermembrane proteins with nuclear DNA fragmentation and
more necrosis.
PMID:21241727
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050115
Ramachandran A et al; Toxicol Appl Pharmacol 251 (3): 226-33 (2011)
Acetaminophen, also known as paracetamol or apap, belongs to the class of organic compounds known as 1-hydroxy-2-unsubstituted benzenoids. These are phenols that are unsubstituted at
the 2-position. Acetaminophen is a drug which is used for temporary relief of fever, minor aches, and pains. Acetaminophen exists as a solid, slightly soluble (in water), and a very weakly acidic
compound (based on its pKa). Acetaminophen has been found throughout all human tissues, and has also been detected in most biofluids, including saliva, feces, blood, and cerebrospinal
fluid. Within the cell, acetaminophen is primarily located in the cytoplasm. Acetaminophen participates in a number of enzymatic reactions. In particular, Acetaminophen can be converted into
NAPQI through the action of the enzymes cytochrome P450 2E1, cytochrome P450 1A2, cytochrome P450 2D6, cytochrome P450 3A4, and cytochrome P450 2A6. In addition, Acetaminophen
and uridine diphosphate glucuronic acid can be converted into acetaminophen glucuronide and uridine 5'-diphosphate through the action of the enzymes UDP-glucuronosyltransferase 1-9,
UDP-glucuronosyltransferase 2B15, UDP-glucuronosyltransferase 1-1, and UDP-glucuronosyltransferase 1-6. In humans, acetaminophen is involved in the acetaminophen metabolism pathway
and the acetaminophen action pathway. Acetaminophen has a bitter taste. Acetaminophen is a potentially toxic compound.
All Tissues
Cytoplasm
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Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
FDA Drugs
11.2 Uses
EPA CPDat Chemical and Product Categories
MEDICATION
MEDICATION (VET)
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.
Mitchell SC, Waring RH; Aminophenols. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2014). NY, NY: John Wiley & Sons. Online Posting Date: September 15, 2000
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Preparation: ... Wilbert, De Angelis, United States of America patent 2998450 (1961 to Warner-Lambert).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
11.4 Formulations/Preparations
Table: Acetaminophen Preparations
Route of
Dosage Form Strength Brand or Generic Name (Manufacturer)
Administration
Oral Capsules 500 mg Acetaminophen Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
167 mg/5 Tylenol Extra-Strength Adult (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary)
Oral Solution
mL name)
100 Tylenol Concentrated Drops Infant's (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic
Oral Solution
mg/mL (nonproprietary) name)
160 mg/5
Oral Suspension Tylenol Oral Suspension Chilcren's (McNeil)
mL
160 mg/5
Oral Suspension Tylenol Oral Suspension Infant's (McNeil)
mL
Tylenol Regular Strength, scored (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic
Oral Tablets 325 mg
(nonproprietary) name)
Tylenol Extra-Strength Rapid Release Gelcaps (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic
Oral Tablets 500 mg
(nonproprietary) name)
Anacin Aspirin Free Extra Strength caplets (Insight) Available from one or more manufacturer, distributor, and/or repackager by generic
Oral Tablets, film-coated 500 mg
(nonproprietary) name)
Oral Tablets, orally disintegrating 160 mg Tylenol Meltaways Junior Strength (McNeil)
Rectal Suppositories 120 mg Acephen (G&W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Rectal Suppositories 125 mg Acetaminophen Suppositories Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Rectal Suppositories 325 mg Acephen (G&W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Rectal Suppositories 650 mg Acephen (G&W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
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.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69
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.)
Kavaler AR; Chemical Marketing Reporter 234 (25): 50 (1988)
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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.
Jones OAH et al; Water Res 36: 1202-11 (2002)
Production volumes for non-confidential chemicals reported under the Inventory Update Rule.
1990 No Reports
2002 No Reports
US EPA; Non-confidential Production Volume Information Submitted by Companies for Chemicals Under the 1986-2002 Inventory Update Rule (IUR). Acetamide, N-(4-hydroxyphenyl)- (103-90-2). Available from, as of
March 6, 2014: http://epa.gov/cdr/tools/data/2002-vol.html
Production volume for non-confidential chemicals reported under the 2006 Inventory Update Rule. Chemical: Acetamide, N-(4-hydroxyphenyl)-. Aggregated National Production Volume: <
500,000 pounds.
US EPA; Non-Confidential 2006 Inventory Update Reporting. National Chemical Information. Acetamide, N-(4-hydroxyphenyl)- (103-90-2). Available from, as of March 6, 2014: http://cfpub.epa.gov/iursearch/index.cfm
Non-confidential 2012 Chemical Data Reporting (CDR) information on the production and use of chemicals manufactured or imported into the United States. Chemical: Acetamide, N-(4-
hydroxyphenyl)-. National Production Volume: 1,768,884 lb/yr.
USEPA/Pollution Prevention and Toxics; 2012 Chemical Data Reporting Database. Acetamide, N-(4-hydroxyphenyl)- (103-90-2). Available from, as of March 6, 2014: http://java.epa.gov/oppt_chemical_search/
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12 Identification
Acetaminophen is determined by reverse phase liquid chromatography using methanol-acetic acid mobile phase and ultraviolet detection at 280 nm in single component drug tablets and in
multi-component tablets containing aspirin and caffeine.
Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990, p. 554 VI 987.12
Analyte: acetaminophen; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1266 (2007)
Analyte: acetaminophen; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1266 (2007)
For more Analytic Laboratory Methods (Complete) data for ACETAMINOPHEN (11 total), please visit the HSDB record page.
Samples used were from rat blood. HPLC method is sensitive enough to detect 0.05 mg/L of phenacetin & 0.25 mg/L of acetaminophen in presence of their metabolites in biological fluids.
PMID:546886
Pang KS et al; J Chromatogr 174 (1): 165 (1979)
The amount of analgesic consumed and the time it was consumed is determined by urine analysis using either thin layer chromatography or colorimetry.
PMID:7165656
Kobbe K, goenechea S; Beitr Gerichtl Med 40: 341 (1982)
High performance liquid chromatography (HPLC) methods were developed for the analysis of acetaminophen in postmortem blood.
PMID:6834796
Wong AS; J Anal Toxicol 7 (1): 33 (1983)
A method for spectrometric measurement of acetaminophen at 615 nm is described which is rapid and precise enough for emergency lab use in blood analysis.
Price CP et al; Clin Chem (Winston-Salem, NC) 29 (2): 358 (1983)
A differential pulse voltammetric method was evaluated for determination of toxic levels of acetaminophen in in vitro human plasma samples.
PMID:722503
Munson JW, abdine A; J Pharm Sci 67 (Dec): 1775 (1978)
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Pictogram(s)
Irritant
Signal Warning
Aggregated GHS information provided by 320 companies from 46 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
Reported as not meeting GHS hazard criteria by 5 of 320 companies. For more detailed information, please visit ECHA C&L website
Of the 44 notification(s) provided by 315 of 320 companies with hazard statement code(s):
H302 (99.05%): Harmful if swallowed [Warning Acute toxicity, oral]
H315 (40.32%): Causes skin irritation [Warning Skin corrosion/irritation]
GHS Hazard Statements
H317 (19.37%): May cause an allergic skin reaction [Warning Sensitization, Skin]
H319 (40%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H412 (50.48%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]
Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from
companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.
Precautionary Statement P261, P264, P270, P272, P273, P280, P301+P312, P302+P352, P305+P351+P338, P321, P330, P332+P313, P333+P313, P337+P313, P362, P363, and P501
Codes (The corresponding statement to each P-code can be found at the GHS Classification page.)
Carcinogenicity - Category 2
Specific target organ toxicity - Repeated exposure - Category 1 (liver, kidney, central nervous system, heart, digestive system), Category 2 (respiratory system, testis)
NITE-CMC
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. ACUTE/CHRONIC HAZARDS: This compound may be harmful
by ingestion and inhalation. It may cause irritation of the skin, eyes, mucous membranes and upper respiratory tract. When heated to decomposition it emits toxic fumes of carbon monoxide,
carbon dioxide and nitrogen oxides. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
CAMEO Chemicals
Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
CAMEO Chemicals
Combustible.
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Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all
affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for
treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth,
throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever
possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO
NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared
to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the
victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
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CAMEO Chemicals
Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Special protective equipment for firefighters: Wear self contained breathing apparatus
for fire fighting if necessary.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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.
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13.5.2 Cleanup Methods
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.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of the work day.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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. STORAGE
PRECAUTIONS: You should protect this material from exposure to light. Keep it away from oxidizing materials and store it under ambient temperatures. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
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Provision to contain effluent from fire extinguishing. Store in an area without drain or sewer access.
Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: 00370, Version 3.6 (Revision Date 11/22/2012). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
Ingestion may cause effects on the kidneys and liver. This may result in impaired functions.
RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for
organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
CAMEO Chemicals
Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143)
respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
Skin and body protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous
substance at the specific workplace.
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
NO open flames.
Protective gloves.
CAMEO Chemicals
CAMEO Chemicals
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Oxidizing agents
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 4, 2014: http://www.fda.gov/cder/ob/
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.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 4, 2014: http://www.fda.gov/cder/ob/
Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx).
Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
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]
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14 Toxicity
14.1.1 Hepatotoxicity
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).
While acetaminophen has few side effects when used in therapeutic doses, recent reports suggest that its standard use can result in severe hypersensitivity reactions including Stevens Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN). Both of these syndromes can be life-threatening and both may be accompanied by evidence of liver injury. However, the hepatic
involvement is usually mild and marked only by asymptomatic mild-to-moderate elevations in serum aminotransferase levels.
The best known form of hepatoxicity from acetaminophen is an acute, serious hepatocellular injury as a result of intentional or unintentional overdose. The injury is due to a direct, toxic effect
of the high doses of acetaminophen. Acetaminophen hepatotoxicity most commonly arises after a suicide attempt using more than 7.5 grams (generally more than 15 grams) as a single
overdose (Case 2). Hepatic injury generally starts 24 to 72 hours after the ingestion with marked elevations in serum ALT and AST (often to above 2000 U/L), followed at 48 to 96 hours by
clinical symptoms: jaundice, confusion, hepatic failure and in some instances death. Evidence of renal insufficiency is also common. Serum aminotransferase levels fall promptly and recovery is
rapid if the injury is not too severe. Similar injury can occur with high therapeutic or supratherapeutic doses of acetaminophen given over several days for treatment of pain and not as a
purposeful suicidal overdose (Case 3). This form of acetaminophen hepatotoxicity is referred to as accidental or unintentional overdose, and usually occurs in patients who have been fasting, or
are critically ill with a concurrent illness, alcoholism or malnutrition, or have preexisting chronic liver disease. Some cases of unintentional overdose occur in patients taking acetaminophen in
combinations with controlled substances (oxycodone, codeine), who take more than recommended amounts over several days in attempts to control pain or withdrawal symptoms. Instances
of unintentional overdose in children are often due to errors in calculating the correct dosage or use of adult sized tablets instead of child or infant formulations. Because acetaminophen is
present in many products, both by prescription and over-the-counter, another problem occurs when a patient ingests full or high doses of several products unaware that several contain
acetaminophen.
Likelihood score: A[HD] (well established cause of liver injury, but severe cases occur only with high doses).
LiverTox
Evaluation: There is inadequate evidence in humans for the carcinogenicity of paracetamol. There is inadequate evidence in experimental animals for the carcinogenicity of paracetamol. Overall
evaluation: Paracetamol is not classifiable as to its carcinogenicity to humans (Group 3).
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at:
http://monographs.iarc.fr/ENG/Classification/index.php, p. 73 438 (1999)
Cough.
Redness.
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ChemIDplus
14.1.8 Interactions
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.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 544
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.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 612
Rate & extent of absorption of per oral dosed paracetamol is reduced by ... concomitant doses of caffeine, by propantheline & metoclopromide, & also by ... cholestyramine.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 128
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.
Hansten P.D. Drug Interactions. 5th ed. Philadelphia: Lea and Febiger, 1985., p. 379
For more Interactions (Complete) data for ACETAMINOPHEN (24 total), please visit the HSDB record page.
LD50 = 338 mg/kg (oral, mouse); LD50 = 1944 mg/kg (oral, rat)[F4133] **Overdose and liver toxicity** Acetaminophen overdose may be manifested by renal tubular necrosis, hypoglycemic
coma, and thrombocytopenia. Sometimes, liver necrosis can occur as well as liver failure. Death and the requirement of a liver transplant may also occur.[Label] Metabolism by the CYP2E1
pathway releases a toxic acetaminophen metabolite known as _N-acetyl-p-benzoquinoneimine_(NAPQI). The toxic effects caused by this drug are attributed to NAPQI, not acetaminophen
alone.[F4133] **Carcinogenesis** Long-term studies in mice and rats have been completed by the National Toxicology Program to study the carcinogenic risk of acetaminophen. In 2-year
feeding studies, F344/N rats and B6C3F1 mice consumed a diet containing acetaminophen up to 6,000 ppm. Female rats showed evidence of carcinogenic activity demonstrated by a higher
incidence of mononuclear cell leukemia at doses 0.8 times the maximum human daily dose (MHDD). No evidence of carcinogenesis in male rats (0.7 times) or mice (1.2 to 1.4 times the MHDD)
was noted.[Label] The clinical relevance of this finding in humans is unknown. **Mutagenesis** Acetaminophen was not found to be mutagenic in the bacterial reverse mutation assay (Ames
test). Despite this finding, acetaminophen tested positive in the in vitro mouse lymphoma assay as well as the in vitro chromosomal aberration assay using human lymphocytes. In published
studies, acetaminophen has been reported to be clastogenic (disrupting chromosomes) when given a high dose of 1,500 mg/kg/day to the rat model (3.6 times the MHDD). No clastogenicity
was observed at a dose of 750 mg/kg/day (1.8 times the MHDD), indicating that this drug has a threshold before it may cause mutagenesis.[Label] The clinical relevance of this finding in
humans is unknown. **Impairment of Fertility** In studies conducted by the National Toxicology Program, fertility assessments have been performed in Swiss mice in a continuous breeding
study. No effects on fertility were seen.[Label] **Use in pregnancy and nursing** The FDA label for acetaminophen considers it a pregnancy category C drug, meaning this drug has
demonstrated adverse effects in animal studies. No human clinical studies in pregnancy have been done to this date for intravenous acetaminophen.[Label] Use acetaminophen only when
necessary during pregnancy.[Label] Epidemiological data on oral acetaminophen use in pregnant women demonstrate no increase in the risk of major congenital malformations.[Label] While
prospective clinical studies examining the results of nursing with acetaminophen use have not been conducted, acetaminophen is found secreted in human milk at low concentrations after oral
administration. Data from more than 15 nursing mothers taking acetaminophen was obtained, and the calculated daily dose of acetaminophen that reaches the infant is about 1 to 2% of the
maternal dose. Caution should be observed when acetaminophen is taken by a nursing woman.[Label]
DrugBank
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
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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.
Emergency and supportive measures. Spontaneous vomiting may delay the oral administration of antidote or charcoal and can be treated with metoclopramide or a serotonin receptor
antagonist such as ondansetron. Provide general supportive care for hepatic or renal failure if it occurs. Emergency liver transplant may be necessary for fulminant hepatic failure.
Encephalopathy, metabolic acidosis, hypoglycemia, and a progressive rise in the prothrombin time are indications of severe liver injury.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 70
Specific drugs and antidotes: Acute single ingestion. If the serum level fall above the upper ("probably toxicity") line on the nomogram or if stat serum levels are not immediately available,
initiate antidotal therapy with N-acetylcysteine (NAC). the effectiveness of NAC depends on early treatment, before the toxic metabolite accumulates; it is of maximal benefit if started within 8-
10 hours and of diminishing value after 12-16 hours; however, treatment should not be withheld even if the delay is 24 hours or more. If vomiting interferes with or threatens to delay oral
acetylcysteine administration, give the NAC IV. If the serum level falls between the "possible toxicity" and "probably toxicity" nomogram lines, strongly consider giving NAC, especially if the
patient is at increased risk for toxicity - for example, if the patient is alcoholic, is taking a drug that induces CYP2E1 activity (eg, isoniazid), or has taken multiple or subacetate overdoses - or if
the time of ingestion is uncertain or unreliable. Many national and international guidelines sue the "possible toxicity" line as the threshold for treating all patients with acute acetaminophen
overdose. If the serum level falls below the lower nomogram line, treatment is generally not indicated unless the time of ingestion is uncertain or the patient is considered to be at particularly
high risk. NOTE: After ingestion of extended-release tablets, which are designed for prolonged absorption, there may be a delay before the peak acetaminophen level is reached. This can also
occur after co-ingestion of drugs that delay gastric emptying, such as opioids and anticholinergics. In such circumstances, repeat the serum acetaminophen level at 8 hours and possible 12
hours. In such cases, it may be prudent to initiate NAC therapy before 8 hours while waiting for subsequent levels.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 71
Specific drugs and antidotes: Chronic or repeated acetaminophen ingestions. Patients may give a history of several doses taken over 24 hour or more, in which case the nomogram cannot
accurately estimate the risk for hepatotoxicity. In such cases, we advise NAC treatment if the amount ingested was more tha 200 mg/kg within a 24 hour persons, 150 mg/kg/day for 2 days, or
100 mg/kg/day for 3 days or more; if the liver enzymes are elevated; if there is detectable acetaminophen in the serum; or if the patient falls within a high-risk group. Treatment may be
stopped 24 hours after the last dose of acetaminophen if the liver enzymes and PT/INR are normal.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 72
Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given
promptly. Although activated charcoal adsorbs some of the orally administered antidote N-acetylcysteine, this effect is not considered clinically important. Do not administer charcoal if more
than 3-4 hours has passed since ingestion unless delayed absorption is suspected ... .
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 72
Enhanced elimination. Hemodialysis effectively removes acetaminophen from the blood but is not generally indicated because antidotal therapy is so effective. Dialysis should be considered
for massive ingestions with very high levels (eg, > 1000 mg/L) complicated by coma and/or hypotension.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 72
Treatment /of overdosage/ consists of two categories. First, the patient who presents early is treated to reduce or prevent acetaminophen-induced injury by the early administration of
acetylcysteine. The late-presenting patient is treated to limit organ injury that arises from acetaminophen toxicity.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 735
The term preventive is applied to the early treatment of patients with acute overdosage. Hepatic injury can be prevented in nearly all patients treated with acetylcysteine within 8 to 10 hours of
an acute ingestion, regardless of the magnitude of the acetaminophen level. Although the mortality is low (11 of 2540 patients, or 0.43%), early treatment is imperative, as no deaths occurred
in this same series in patients treated before 16 hours postingestion. The data indicate that acetylcysteine also has some therapeutic effect for patients who present 10 to 24 hours after
ingestion, although its efficacy diminishes as the time to treatment increases. Some suggestion has been made that treatment performed at even as late as 36 hours may have some benefit.
Therefore, all patients with a single acute ingestion of acetaminophen whose serum acetaminophen level falls above the treatment line should be treated with acetylcysteine.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 584
If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially
and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as possible. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against
time since oral ingestion on a nomogram (Rumack-Matthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/mL at 12 hours. If serum level is
above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the acetaminophen level is below the lower line.
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-
valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean
patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain
medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if
needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures
and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion,
rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings
after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
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/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory
distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as
albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline
(NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with
diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1
/HUMAN EXPOSURE STUDIES/ Three hundred and seven cases of liver injury associated with acetaminophen use were reported to the US Food and Drug Administration (FDA) from January
1998 to July 2001. Sixty percent of these adverse events were categorized as severe life-threatening injury with liver failure (category 4); 40% of patients died. Review of these case reports
indicates that use of higher than recommended daily dosages of acetaminophen results in adverse hepatotoxic effects more often than use of recommended dosages.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2211
/HUMAN EXPOSURE STUDIES/ The Rocky Mountain Poison and Drug Center reported the results of a nationwide study on acetaminophen overdose during pregnancy involving 113 women. Of
the 60 cases that had appropriate laboratory and pregnancy outcome data, 19 occurred in the 1st trimester, 22 during the 2nd trimester, and 19 during the 3rd trimester. In those cases with a
potentially toxic serum level of acetaminophen, early treatment with N-acetylcysteine was statistically associated with an improved pregnancy outcome by lessening the incidence of
spontaneous abortion and fetal death. Only one congenital anomaly was observed in the series and that involved a 3rd trimester overdose with nontoxic maternal acetaminophen serum levels.
Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 9
/HUMAN EXPOSURE STUDIES/ Paracetamol (acetaminophen) is a widely used analgesic drug. It interacts with various enzyme families including cytochrome P450 (CYP), cyclooxygenase (COX),
and nitric oxide synthase (NOS), and this interplay may produce reactive oxygen species (ROS). ... The effects of paracetamol on prostacyclin, thromboxane, nitric oxide (NO), and oxidative
stress in four male subjects who received a single 3 g oral dose of paracetamol /was investigated/. Thromboxane and prostacyclin synthesis was assessed by measuring their major urinary
metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1 a , respectively. Endothelial NO synthesis was assessed by measuring nitrite in plasma. Urinary 15(S)-8-iso-
prostaglanding F2 a was measured to assess oxidative stress. Plasma oleic acid oxide (cis-EpOA) was measured as a marker of cytochrome P450 activity. Upon paracetamol administration,
prostacyclin synthesis was strongly inhibited, while NO synthesis increased and thromboxane synthesis remained almost unchanged. Paracetamol may shift the COX-dependent
vasodilatation/vasoconstriction balance at the cost of vasodilatation. This effect may be antagonized by increasing endothelial NO synthesis. High-dosed paracetamol did not increase oxidative
stress. At pharmacologically relevant concentrations, paracetamol did not affect NO synthesis/bioavailability by recombinant human endothelial NOS or inducible NOS in rat hepatocytes. /It
was concluded/ that paracetamol does not increase oxidative stress in humans.
PMID:24799980
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988730
Trettin A et al; Oxid Med Cell Longev. 2014;2014:212576. doi: 10.1155/2014/212576. Epub 2014 Mar 31
/HUMAN EXPOSURE STUDIES/ ... Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute
liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured
at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing
transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment
of liver tissue was performed. Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients
compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755
(0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the
portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower
apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence
of cellular proliferation with an absence of histological evidence of apoptosis. Hepatocellular apoptosis occurs in the early phases of human acetaminophen-induced acute liver failure, peaking
on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated
levels of M30 are likely to reflect epithelial cell death in extrahepatic organs.
PMID:23949472
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3939768
Possamai LA et al; Crit Care Med 41 (11): 2543-50 (2013)
For more Human Toxicity Excerpts (Complete) data for ACETAMINOPHEN (46 total), please visit the HSDB record page.
/LABORATORY ANIMALS: Acute Exposure/ ... Acetaminophen was administered to 4 adult cats. A marked degree of cyanosis was seen in these animals within 4 hr after administration of single
tablet containing 325 mg ... due to hypoxia associated with conversion of hemoglobin to methemoglobin. In addition, anemia, hemoglobinuria, and icterus were eventually seen in the cats.
Hemolysis of red blood cells was responsible for development of anemia and hemoglobinuria. Icterus was attributed to both lysis of erythrocytes and hepatic necrosis. Facial edema was also
observed in 3 of the 4 experimental cats.
Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 304
/LABORATORY ANIMALS: Acute Exposure/ Postmitochondrial supernatants isolated from the livers of mature rats (3-6 mo old) 2 hr or more after admin of a single large oral dose of
paracetamol (800 mg/kg) showed rapid rates of lipid peroxidation. In similar expt with old rats (27-30 mo old) the time between admin of paracetamol and the onset of lipid peroxidation was
much longer, up to 6 hr.
PMID:6836594
Barber DJ et al; Toxicol Lett 15 (4): 283 (1983)
/LABORATORY ANIMALS: Acute Exposure/ Male Wistar rats were fasted 24 hr and administered a single dose of paracetamol/water suspension (2 g paracetamol/kg) by gavage. Rats were
killed, and liver and blood samples taken at 0, 6, 9, 12, and 24 hr post paracetamol administration. Hepatic reduced glutathione levels were lowered within 6 hr after paracetamol treatment, and
remained so until returning to control levels at 12-24 hr. Serum glutamate pyruvate transaminase (SGPT) levels were increased from control (n= 7) levels of 30-40 mU/mL to 700-3000 mU/mL
at 24 hr after paracetamol administration. Blood glucose concentrations of paracetamol treated rats (n= 13) were 5.85 +/- 0.50 mM compared to the control values of 5.28 +/- 0.36 mM. Based
on trypan blue exclusion, paracetamol-induced necrosis around the central vein was noted at 9-12 hr and was much more extensive at 24 hr after treatment. A concurrent activation of
glycogen phosphorylase in perivenous hepatocytes and an increase in periportal hepatocyte glycogen content was observed at 12 hr post treatment.
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PMID:3424388
Jepson MA et al; Toxicology 47 (3): 325-37 (1987)
/LABORATORY ANIMALS: Acute Exposure/ Acetaminophen ... an analgesic and antipyretic, is without known ocular side effects, with the exception that in genetically very special mice it can
cause irreversible opacification of the anterior portion of the lens when a large dose is given ip.
Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 32
For more Non-Human Toxicity Excerpts (Complete) data for ACETAMINOPHEN (36 total), please visit the HSDB record page.
In adults, hepatic toxicity rarely has occurred with acute overdoses of less than 10 g, although hepatotoxicity has been reported in fasting patients ingesting 4-10 g of acetaminophen. Fatalities
are rare with less than 15 g.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2210
LC50; Species: Anas platyrhynchos (Mallard duck) age 9 days; diet >5900 ppm for 8 days
USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Colinus virginianus (Northern Bobwhite Quail) age 14 days; diet >5900 ppm for 8 days
USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) as cited in the ECOTOX database. Available from, as of January 16, 2014
LD50; Species: Colinus virginianus (Northern Bobwhite Quail) age 22 weeks; oral via capsule >2250 mg/kg
USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) as cited in the ECOTOX database. Available from, as of January 16, 2014
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/
Richards SM, Cole SE; Ecotoxicology 15 (8): 647-656 (2006) as cited in the ECOTOX database. Available from, as of January 16, 2014
EC50; Species: Xenopus laevis (African clawed toad) embryo; Conditions: freshwater, renewal, 23 °C, FETAX solution, unactivated; Concentration: 143300 ug/L for 96 hr (95% confidence interval:
132900-154600 ug/L); Effect: increased abnormal development (gut miscoiling, craniofacial defects, abnormal mouth development, muscular kinking, heart maldevelopment, pericardial and
ophthalmic edema /formulated product/
Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014
EC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal, 23 °C, FETAX solution, activated with Aroclor 1254-induced rat liver microsomes; Concentration:
20100 ug/L for 96 hr (95% confidence interval: 8900-45800 ug/L); Effect: increased abnormal development (gut miscoiling, hypognathia, lateral body flexure, skeletal kinking, microencephaly
/formulated product/
Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014
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LC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal, 23 °C, FETAX solution, unactivated; Concentration: 191100 ug/L for 96 hr (95% confidence interval:
168500-216700 ug/L) /formulated product/
Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal, 23 °C, FETAX solution, activated with Aroclor 1254-induced rat liver microsomes; Concentration:
49600 ug/L for 96 hr (95% confidence interval: 45500-54200 ug/L) /formulated product/
Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Artemia salina (Brine Shrimp) age 2-3 instar larva; Conditions: saltwater, static; Concentration: 3820 umol/L for 24 hr /formulated product/
Calleja MC, Persoone G; ATLA Altern Lab Anim 20: 396-405 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Streptocephalus proboscideus (Fairy Shrimp) age 2-3 instar larva; Conditions: freshwater, static, 25 °C; Concentration: 196 umol/L for 24 hr /formulated product/
Calleja MC, Persoone G; ATLA Altern Lab Anim 20: 396-405 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014
EC50; Species: Daphnia magna (Water Flea) age 6-24 hr; Conditions: freshwater, static, 20 °C, pH > or =7.0; Concentration: 13000 ug/L for 24 hr (95% confidence interval: 6000-32000 ug/L);
Effect: intoxication, immobilization /formulated product/
Kuhn R et al; Water Res 23 (4): 495-499 (1989) as cited in the ECOTOX database. Available from, as of January 16, 2014
EC50; Species: Daphnia magna (Water Flea) age 6-24 hr; Conditions: freshwater, static, 20 °C, pH > or =7.0; Concentration: 9200 ug/L for 48 hr (95% confidence interval: 6100-14000 ug/L);
Effect: intoxication, immobilization /formulated product/
Kuhn R et al; Water Res 23 (4): 495-499 (1989) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Daphnia magna (Water Flea) age <24 hr neonate; Conditions: freshwater, static, 20 °C; Concentration: >32 ug/L for 48 hr /98-101% purity/
Brun GL et al; Environ Toxicol Chem 25 (8): 2163-2176 (2006) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Daphnia magna (Water Flea) age <24 hr neonate; Conditions: freshwater, static, 25 °C, pH 7.8, hardness 170 mg/L CaCO3, alkalinity 110 mg/L CaCO3; Concentration: 20100 ug/L
for 48 hr /formulated product/
Han GH et al; Environ Toxicol Chem 25 (1): 265-271 (2006) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Oryzias latipes (Japanese Medaka) length 2.0 cm; Conditions: freshwater, renewal, 25 °C, dissolved oxygen >80% saturated; Concentration: >160000 ug/L for 48 hr /formulated
product/
Kim Y et al; Environ Int 33 (3): 370-375 (2007) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Oryzias latipes (Japanese Medaka) length 2.0 cm; Conditions: freshwater, renewal, 25 °C, dissolved oxygen >80% saturated; Concentration: >160000 ug/L for 96 hr /formulated
product/
Kim Y et al; Environ Int 33 (3): 370-375 (2007) as cited in the ECOTOX database. Available from, as of January 16, 2014
LC50; Species: Pimephales promelas (Fathead minnow) age 33 days, length 24.6 mm, weight 0.246 g; Conditions: flow through, 24.7 °C, dissolved oxygen 5.9 mg/L, hardness 51.0 mg/L CaCO3,
alkalinity 45.0 mg/L CaCO3, pH 7.4; Concentration: 814 mg/L for 96 hr /99% purity/
Brooke, L.T., D.J. Call, D.T. Geiger and C.E. Northcott (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Superior, WI: Center for Lake Superior Environmental Studies Univ. of Wisconsin
Superior, 1984., p. 291
EC50; Species: Lemna minor (Duckweed) age 3-4 fronds; Conditions: freshwater, pH 5.5-8.0; Concentration: >200000 ug/L for 168 hr /formulated product/
Kaza M et al; Fresenius Environ Bull 16 (5): 524-531 (2007) as cited in the ECOTOX database. Available from, as of January 16, 2014
/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.
PMID:17223195
Kim Y et al; Environ Int 33 (3): 370-5 (2007)
/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
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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.
PMID:24816177
Ramos AS et al; Environ Toxicol Pharmacol 37 (3): 1221-1228 (2014)
/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.
Johnston JJ, et al; Environ Sci Technol 36 (17): 3827-33 (2002)
EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to
explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21)
collaboration. /The title compound was tested by ToxCast and/or Tox21 assays; See the data in Chemical Explorer/[USEPA; ICSS Dashboard Application; Available from, as of March 28, 2014:
http://actor.epa.gov/dashboard/]
The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies",
"Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in
preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical[Available from, as of March 5, 2014: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?
fuseaction=ntpsearch.searchresults&searchterm=103-90-2]
14-DAY STUDIES. Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen, and mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm
acetaminophen. There were no deaths among any groups during the study; the final mean body weight of male rats that received 12,500 ppm was significantly lower than that of the controls.
Final mean body weights of male and female mice and female rats that received acetaminophen were similar to those of the controls. Feed consumption by male and female rats that received
12,500 ppm acetaminophen was lower than that of the controls; feed consumption by all other exposed groups was higher than that of the controls. 13-WEEK STUDIES. Rats and mice were fed
diets containing 0, 800, 1,600, 3,200, 6,200, 12,500, or 25,000 ppm acetaminophen. Two male and two female rats, and one male and one female mouse that received 25,000 ppm, and two male
mice that received 12,500 ppm died from acetaminophen-related toxicity before the end of the studies. Final mean body weights of male and female rats and mice that received 12,500 or
25,000 ppm were lower than those of the controls. The patterns of feed consumption and reduced body weights that occurred among rats and mice that received diets containing 12,500 or
25,000 ppm were indicative of poor feed palatability. Acetaminophen-related lesions were observed in the liver (necrosis, chronic active inflammation, hepatocytomegaly), kidney (tubule cast,
tubule necrosis, tubule regeneration), reproductive organs (atrophy of testis, ovary, and uterus), thymus and lymph nodes (lymphoid depletion) of rats that received 25,000 ppm, and of the live
(chronic active inflammation, hepatocytomegaly) and testis (atrophy) of male rats receiving 12,500 ppm. Compound-related lesions in mice were found in the liver (hepatocytomegaly, focal
calcification, pigmentation, necrosis) of males that received 6,200, 12,500, or 25,000 ppm and females that received 12,000 or 25,000 ppm. Dose selection for the 2-year studies was based on
reduced body weights and the liver lesions observed in rats and mice at 12,500 and 25,000 ppm. 2-YEAR STUDIES Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given
continuously to groups of 60 rats and mice of each sex for up to 104 weeks. After 65 weeks of exposure, 10 animals from each group were evaluated for histopathology and for hematology,
urinalysis, and clinical chemistry parameters. Survival and mean body weights of rats that received acetaminophen were similar to those of the controls throughout the study. The average
severity of nephropathy was increased in exposed male and female rats. In males this was associated with an increased incidence of parathyroid hyperplasia (renal hyperparathyroidism). The
incidence of focal renal tubule hyperplasia was also increased in exposed male rats. The incidence of mononuclear cell leukemia was increased in exposed female rats and was significantly
increased in the 6,000 ppm group (9/50; 17/50; 15/50; 24/50). Survival of exposed and control mice was similar throughout the study. Mean body weights of mice that received acetaminophen
were generally lower than those of the controls throughout the study. Although the incidence of thyroid follicular cell hyperplasia increased with dose among groups of exposed male and
female mice, there was no increase in the incidence of follicular cell neoplasms. Renal tubule hyperplasia occurred in one low-dose and two high-dose males and a renal tubule adenoma was
present in one low-dose and one high-dose male. GENETIC TOXICOLOGY. Acetaminophen was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or
without S9. In cytogenetic tests with Chinese hamster ovary cells, acetaminophen induced sister chromatid exchanges and chromosomal aberrations in both the presence and absence of S9.
CONCLUSIONS Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm.
There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was no evidence of
carcinogenic activity of acetaminophen in male and female B6C3F1 mice that received 600, 3,000, or 6,000 ppm. Nonneoplastic lesions associated with exposure to acetaminophen included
increased severity of nephropathy and increased incidences of renal tubule hyperplasia and parathyroid hyperplasia in male rats, increased severity of nephropathy in female rats, and increased
incidences of thyroid follicular cell hyperplasia in male and female mice.
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 U.S. Department of Health and Human Services,
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
Acetaminophen (ACET) ... was tested for its effects on reproduction & fertility in CD-1 mice, following the RACB protocol. Data on body weights, clinical signs, & food & water consumption
from a 2 wk dose-range-finding study (Task 1) were used to set exposure levels for the Task 2 continuous cohabitation phase at 0.25%, 0.5%, & 1.0% in the diet. Feed consumption was reduced
only in females at the top dose level, by 10-20%. Measured body weight & feed consumption allowed exposure to be estimated as nearly equal to 370, 770, & 1400 mg/kg/day. During Task 2,
4 animals died: 2, 1, & 1 each in the low, middle, & high dose groups. During Task 2, the number of litters/pair decreased by 3% for the high dose group. No changes were noted in the number
of pups/litter, viability, or in adjusted pup weight. The slight reduction in number of litters/pair was judged to be too small to yield a detectable change during the statistically-less-powerful
Task 3 crossover mating, so no crossover test was conducted. For the F1 evaluation, the last litter in Task 2 from all dose groups was nursed to weaning, & reared on the diet consumed by their
parents. F1 pup body weights were reduced at all doses for both sexes by nearly equal to 6-18%. Pup body weight gain to weaning was also reduced for the medium & high dose males (17%
& 34%), & for females at all doses (10-28%). All dose groups were reared consuming the same diet provided to their parents. The body weight differences that were seen during nursing were
reduced, but still present, at the time of mating. At the F1 mating, the F2 pup weight adjusted for litter size was decreased by 11% at the high dose level. No other reproductive endpoints were
affected. After the F2 pups were delivered & evaluated, the F1 adults from only the control & high dose groups were killed & necropsied. Compared to controls, the high dose males weighed
10% less, while organ weights were not affected. Sperm abnormalities increased from 7% (controls) to 16% at the high dose. High dose females weighed 8% less, while adjusted liver weight
was increased by 10%. In summary, the greatest toxicity produced by acetaminophen in the diet of Swiss mice was on the growing neonate (reduced weight gain during nursing). Fertility
endpoints (ability to bear normal numbers of normal-weight young) were generally not affected.
Department of Health & Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Acetaminophen : (CAS # 103-90-2): Reproduction and Fertility Assessment in CD-1 Mice When
Administered in the Feed, NTP Study No. RACB83079 (November 21, 1984) Available from, as of August 15, 2002: http://ntp.niehs.nih.gov/index.cfm?objectid=0847F35A-0850-D1E7-B02ED4DDD150F990
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Acetaminophen is contraindicated: in patients with known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation and in patients with severe hepatic
impairment or severe active liver disease.
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
Because there is some evidence that chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, chronic alcoholics should be cautioned to avoid
regular or excessive use of acetaminophen, or alternatively, to avoid chronic ingestion of alcohol.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone
disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development. To evaluate whether prenatal exposure to acetaminophen increases the risk for developing
attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children, /the researchers/ studied 64,322 live-born children and mothers enrolled
in the Danish National Birth Cohort during 1996-2002. Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6
months after child birth. To ascertain outcome information /the researchers/ used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties
Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly
Ritalin) for children from the Danish Prescription Registry. /The researchers/ estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral
problems in children after prenatal exposure to acetaminophen. More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen
during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or
having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure
response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend <
0.001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother's mental health problems, or other potential confounders /the researchers/
evaluated. Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent,
these results are of public health relevance but further investigations are needed.
PMID:24566677
Liew Z et al; JAMA Pediatr 168 (4):313-20 (2014)
Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia
(e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance = 30 mL/min).
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
The binding of acetaminophen to plasma proteins is low (ranging from 10% to 25%), when given at therapeutic doses.[Label]
DrugBank
The substance is toxic to aquatic organisms. It is strongly advised not to let the chemical enter into the environment.
Acetaminophen's production and use as an analgesic and the production and use in the manufacture of azo dyes and photographic chemicals may result in its release to the environment
through various waste streams. If released to air, an estimated vapor pressure of 6.3X10-5 mm Hg at 25 °C indicates acetaminophen will exist in both the vapor and particulate phases in the
atmosphere. Vapor-phase acetaminophen will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to
be 22 hrs. Particulate-phase acetaminophen will be removed from the atmosphere by wet and dry deposition. Acetaminophen absorbs light at wavelengths >290 nm and, therefore, may be
susceptible to direct photolysis by sunlight. If released to soil, acetaminophen is expected to have very high mobility based upon an estimated Koc of 21. Volatilization from moist soil surfaces
is not expected to be an important fate process based upon an estimated Henry's Law constant of 8.8X10-10 atm-cu m/mole. Acetaminophen is not expected to volatilize from dry soil surfaces
based upon its vapor pressure. The biodegradation half-lives for non-adapted, phenol-adapted, and cresol-adapted activated sludge were 21, 40, and 13 days, respectively, suggesting that
biodegradation may be an important environmental fate process in soil and water. If released into water, acetaminophen is not expected to adsorb to suspended solids and sediment based
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upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3
suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups
that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to acetaminophen may occur through inhalation and dermal contact with this compound at workplaces
where acetaminophen is produced or used. Monitoring and use data indicate that the general population may be exposed to acetaminophen via ingestion of drinking water, and ingestion and
dermal contact with this compound and other products containing acetaminophen. Exposure to acetaminophen among the general population may be widespread through use of the drug as
an analgesic. (SRC)
Acetaminophen's administration and use as an analgesic and production and use in the manufacture of azo dyes and photographic chemicals(1) may result in its release to the environment
through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck index. 15th ed. Whitehouse Station, NJ: Merck & Co., p 11 (2013)
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).
(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014:
http://logkow.cisti.nrc.ca/logkow/search.html (3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (4)
Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, (1989) (5) Yalkowsky SH et al; Handbook of Aqueous Solubility Data. 2nd ed.
Boca Raton, FL: CRC Press p. 492 (2010) (6) Yonezawa Y et al; Kogai Shigen Kenkyusho Iho 15: 75-86 (1985)
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).
(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014:
http://logkow.cisti.nrc.ca/logkow/search.html (3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (4)
Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data
Compilation. Washington, D.C.: Taylor and Francis, (1989) (6) Yalkowsky SH et al; Handbook of Aqueous Solubility Data. 2nd ed. Boca Raton, FL: CRC Press p. 492 (2010) (7) Franke C et al; Chemosphere 29: 1501-14 (1994)
(8) Yonezawa Y et al; Kogai Shigen Kenkyusho Iho 15: 75-86 (1985)
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).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014:
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) NIST; NIST Chemistry WebBook. Acetaminophen (103-90-2). NIST Standard Reference Database
No. 69, June 2005 Release. Washington, DC: US Sec Commerce. Available from, as of Mar 6, 2014: http://webbook.nist.gov
AEROBIC: Acetaminophen has been categorized as readily biodegradable following acclimation(1). A half-life of 20 days has been reported for acetaminophen using an activated sludge
inoculum(2). Half-lives of 40 and 17 days were observed when using activated sludge inoculums acclimated to phenol(3) and cresol(4), respectively. Acetaminophen reached 94% of its
theoretical BOD in 6 days using an activated sludge inoculum and the Zahn-Wellens test(5). The rate constants for non-adapted, phenol-adapted, and cresol-adapted activated sludge (sludge
concentrations of 500, 10, and 50 mg/L) were 0.141X10-2, 0.713X10-3, and 0.215X10-2 1/hr, respectively(6); half-lives are 21, 40, and 13 days, respectively(SRC). Acetaminophen, present at 100
ug/L, exhibited biodegradation rates of 0.014/hr and 0.00051/hr in 5 days using Tamlya and Tsumeta River water (Japan), respectively, and the OECD 301-A river die-away test. The
corresponding half-lives are 50 and 1400 hours, respectively(7).
(1) Richardson ML, Bowron JM; J Pharm Pharmacol 37: 1-12 (1985) (2) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 12: 37-56 (1983) (3) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 12: 49-54 (1983) (4) Urushigawa
Y et al; Kogai Shigen Kenkyusho Iho 13: 59-65 (1984) (5) Wellens H; Z Wasser Abwasser Forsch 23: 85-98 (1990) (6) Yonezawa Y et al; Kogai Shigen Kenkyusho Iho 15: 75-86 (1985) (7) Yamamoto H et al; Water Res 43:
351-362 (2009)
AEROBIC: Occurrence and removal efficiencies of fifteen pharmaceuticals were investigated in a conventional municipal wastewater treatment plant in Michigan. Concentrations of these
pharmaceuticals were determined in both wastewater and sludge phases by a high-performance liquid chromatograph coupled to a tandem mass spectrometer. Detailed mass balance analysis
was conducted during the whole treatment process to evaluate the contributing processes for pharmaceutical removal. Among the pharmaceuticals studied, demeclocycline, sulfamerazine,
erythromycin and tylosin were not detected in the wastewater treatment plant influent. Other target pharmaceuticals detected in wastewater were also found in the corresponding sludge
phase. The removal efficiencies of chlortetracycline, tetracycline, sulfamerazine, acetaminophen and caffeine were >99%, while doxycycline, oxytetracycline, sulfadiazine and lincomycin
exhibited relatively lower removal efficiencies (e.g., <50%). For sulfamethoxazole, the removal efficiency was approximately 90%. Carbamazepine manifested a net increase of mass, i.e. 41%
more than the input from the influent. Based on the mass balance analysis, biotransformation is believed to be the predominant process responsible for the removal of pharmaceuticals (22% to
99%), whereas contribution of sorption to sludge was relatively insignificant (7%) for the investigated pharmaceuticals.
PMID:22494528
Gao P et al; Chemosphere 88(1):17-24 (2012)
ANAEROBIC: Acetaminophen, present at 50 ppm carbon, reached 93% of its theoretical methane production in 56 days using a digestor sludge inoculum fortified with mineral salts(1). A 30-
75% theoretical methane production resulted when using inoculum from a secondary digestor(1).
PMID:16346484
Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC239700
(1) Shelton DR, Tiedje JM; Appl Environ Microbiol 47: 449-69 (1984)
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The rate constant for the vapor-phase reaction of acetaminophen with photochemically-produced hydroxyl radicals has been estimated as 1.8X10-11 cu cm/molecule-sec at 25 °C(SRC) using a
structure estimation method(1). This corresponds to an atmospheric half-life of about 22 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Acetaminophen is
not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Acetaminophen absorbs at wavelengths >290
nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). Acetaminophen, present at 100 ug/L in 30-mL quartz test tubes and exposed to direct sunlight, exhibited half-
lives of 56 and 35 hours in August 2006 and May 2007, respectively(4). Acetaminophen was present in a mixture of eight pharmaceuticals which were added to aquatic outdoor field
microcosms at low, medium, high, and ultra-high concentrations (acetaminophen concentrations of 0.83, 33.98, 132.00 and 2,190 ug/L, respectively)(5). Half-lives in the field were 1, 0.9, 0.7. and
1.1 days, respectively. Lab results suggest that neither hydrolysis nor biodegradation were important environmental fate processes. However, photodegradation did play an important role in
limiting the presence of the test compounds(4). Loss due to indirect photolysis reactions involving the OH radical was 100% in 15 days with no loss observed in controls(5,6).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (2) Lyman WJ et al; Handbook of Chemical Property
Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) NIST; NIST Chemistry WebBook. CHEMICAL (103-90-2). NIST Standard Reference Database No. 69, June 2005 Release. Washington, DC: US Sec
Commerce. Available from, as of Mar 6, 2014: http://webbook.nist.gov (4) Yamamoto H et al; Water Res 43: 351-362 (2009) (5) Lam MW et al; Environ Sci Toxicol 37: 899-907 (2003) (6) Lam MW et al; Environ Toxicol
Chem 23: 1431-40 (2004)
88% Transformation of 10 umol/L acetaminophen in pure water at neutral pH using 57 umol/L hypochlorite (4 ppm as Cl2) was observed in a test designed to simulate chlorination carried out
over time to simulate wastewater disinfection. This treatment produced 11 discernable products, including the toxic compounds 1,4-benzoquinone and N-acetyl-p-benzoquinone imine, 25%
and 1.5% of the initial acetaminophen concentration, respectively, in 1 hour reaction time(1).
(1) Bender M, Maccrehan WA; Environ Sci Technol 40: 516-522 (2006)
An estimated BCF of 3 was calculated in fish for acetaminophen(SRC), using a log Kow of 0.46(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests
the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: http://logkow.cisti.nrc.ca/logkow/search.html (2) US EPA; Estimation Program
Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm/ (3) Franke C et al; Chemosphere 29: 1501-14 (1994)
The Koc of acetaminophen is estimated as 21(SRC), using a log Kow of 0.46(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests
that acetaminophen is expected to have very high mobility in soil. The pKa of acetaminophen is 9.38(4), indicating that this compound will exist partially in the anion form in the environment
and anions generally adsorb less strongly to soils containing organic carbon and clay than their neutral counterparts(5). However, low mobilty was observed in soils with a high organic content.
Kd values of 46 and 36 in clayey silt and silty sand, respectively, have been reported when the test compound was applied in standard dilution(6). Kd values of 45 and 41 in clayey silt and silty
sand, respectively, have been reported when acetaminophen was applied as a test sludge; the average Kd value of 42 indicated low mobility(6). Acetaminophen, present at <0.009 ug/L, was not
detected in leachate water (treated effluent from a muncipal wastewater treatment facility) following a 23-day soil column leaching experiment using Mohall-Laveen sandy loam (detection limit
= 0.009 ug/L)(7).
(1) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: http://logkow.cisti.nrc.ca/logkow/search.html (2) US EPA; Estimation Program
Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Dastmalchi S et al; J Sch Pharm., Med
Sci Univ Tehran 4: 7-14 (1995) (5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000) (6) Kreuzig R et al; Fresnius Environ
Bull 12: 550-8 (2003) (7) Cordy GE et al; Ground Water Monit Remed 24: 58-69 (2004)
The Henry's Law constant for acetaminophen is estimated as 8.9X10-10 atm-cu m/mole(SRC) derived from its vapor pressure, 6.29X10-5 mm Hg(1), and water solubility, 1.4X10+4 mg/L(2). This
Henry's Law constant indicates that acetaminophen is expected to be essentially nonvolatile from water and moist soil surfaces(3). Acetaminophen is not expected to volatilize from dry soil
surfaces(SRC) based upon its vapor pressure(1).
(1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, (1989) (2) Yalkowsky SH et al; Handbook of Aqueous Solubility Data. 2nd ed.
Boca Raton, FL: CRC Press p. 492 (2010) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
GROUNDWATER: Acetaminophen (reporting limit 0.009 ug/L) was not detected in the leachate plume down gradient of the Norman municipal landfill in central Oklahoma, sampled Sept 6,
2000(1).
(1) Barnes KK et al; Ground Water Monit Remed 24: 119-26 (2004)
GROUNDWATER: Dewatered municipal biosolids (DMBs) were applied to a field at a rate of approximately 22 Mg dw/ha in Oct 2008. Pharmaceuticals and personal care products (PPCPs) were
monitored in groundwater, tile drainage, soil, DMB aggregates incorporated into the soil post-land application, and in the grain of wheat grown on the field for a period a about 1 year
following application. Over 80 PPCPs were analyzed in the source DMB. PPCPs selected for indpeth monitoring included: antibiotics (tetracyclines, fluoroquinolones), bacteriocides (triclosan,
triclocarban), beta-blockers (atenolol, propranolol, metaprolol), antidepressants (flouxetine, citalopram, venlafaxine, sertraline), antifungals (miconazole), analgesics (acetaminophen,
ibuprofen) and antiiconvulsants (carbamazepine). PPCPs in tile were observed twice, approximately 3 weeks and 2 months post-application. Of all PPCPs measured in tile drainage, only
carbamazepine, ibuprofen, acetaminophen, triclosan, triclocarban, venlafaxine, and citalopram were detected (5-74 ng/L). PPCPs were not detected in groundwater >2 m depth below the soil
surface, and concentrations above detection limits at 2 m depth were only observed once just after the first rain event post-application. In groundwater, all compounds in tile, except
carbamazepine, acetaminophen and citalopram, were detected (10-10 ng/L). PPCPs were detected in DMB aggregates incorporates in soil up to 1 year post-application, with miconazole and
fluoxetine having the lowest percent reductions over 1 year (approximately 50%). For several compounds in these aggregates, concentration declines were of exponential decay form. No
PPCPs were detected in the grain of wheat planted post-application on the field. No PPCPs were ever detected in water, soil or grain samples from the reference plot, where no DMB was
applied.
PMID:22300554
Gottschall N et al; Chemosphere 87(2): 194-203 (2012)
DRINKING WATER: Acetaminophen was detected in samples from Jefferson Parish East Bank drinking water plant, New Orleans, Louisiana at concentrations of 0.2, not detected to 0.2, and not
detected to 0.1 ng/L from the Mississippi River, precipitator, and finished water, respectively, sampled from September - November, 2001(1). A drinking water treatment plant in Windsor,
Ontario, Canada had a concentration of 0.2 ng/L in finished water(1).
PMID:12826389
(1) Boyd GR et al; Sci Total Environ 311: 135-49 (2003)
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Hazardous Substances Data Bank (HSDB)
SURFACE WATER: Acetaminophen was not detected in samples from Lake Pontchartrain nor the Mississippi River at the Bonnet Carrie Spillway, New Orleans, Louisiana (detection limit 45 ng/L),
sampled from September - November, 2001(1). It was not detected in intake water from the Detroit River to a drinking water treatment plant in Windsor, Ontario, Canada(1). As part of a
National Reconnaissance of 139 US streams across 30 state conducted from 1999 through 2000, acetaminophen concentration was detected in 23.8% of 84 samples, maximum and median
concentrations of 10 and 0.11 ug/L, respectively, reporting limit 0.009 ug/L(2). Acetaminophen was tested for in 23 stream locations of 10 Iowa cities; high flow sample maximum concentration
was 0.059 ug/L, 43.5% frequency, not detected during normal-flow concentrations, and maximum low-flow concentration was 1.95 ug/L and 20.0% frequency(3). Acetaminophen exhibited a 0%
frequency of detection in 7 surface water samples from the Great Lakes, detection limit 0.0045 ug/L(4). The compound was present at 10.1 ng/L in samples from Dutch Coast of the North Sea,
collected from 1996 to 2005(5).
(1) Boyd GR et al; Sci Total Environ 311: 135-49 (2003) (2) Kolpin DW et al; Environ Sci Technol 36: 1202-11 (2002) (3) Kolpin DW et al; Sci Total Environ 348: 119-30 (2004) (4) Klecka G et al; Rev Environ Contam Toxicol
207: 1-93 (2010) (5) Walraven N, Laane RWPM; Rev Environ Contam Toxicol 199: 1-18 (2008)
Acetaminophen was detected, not quantified in four of eight secondary effluents from publicly-owned treatment works in Illinois, sampled from February to June, 1980(1). It was not detected
in effluent from an industrial plant sampled as part of this same study(1). Acetaminophen was detected in sewage treatment plant effluent from Louisiana at concentrations of 1.1 and 1.2 ng/L,
sampled from September - November, 2001(2). It was not detected in effluent from a pilot plant in Windsor, Ontario, Canada(2).
(1) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (2) Boyd GR et al; Sci Total Environ 311: 135-49 (2003)
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.
Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 11
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.
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: ttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?
setid=c5177abd-9465-40d8-861d-3904496d82b7
According to the 2006 TSCA Inventory Update Reporting data, the number of persons reasonably likely to be exposed in the industrial manufacturing, processing, and use of acetaminophen is
1 to 99; the data may be greatly underestimated(1).
(1) US EPA; Inventory Update Reporting (IUR). Non-confidential 2006 IUR Records by Chemical, including Manufacturing, Processing and Use Information. Washington, DC: U.S. Environmental Protection Agency. Available
from, as of Mar 6, 2014: http://cfpub.epa.gov/iursearch/index.cfm
NIOSH (NOES Survey 1981-1983) has statistically estimated that 65,107 workers (56,260 of these were female) were potentially exposed to acetaminophen in the US(1). Occupational exposure
to acetaminophen may occur through inhalation and dermal contact with this compound at workplaces where acetaminophen is produced or used(SRC). Monitoring and use data indicate that
the general population may be exposed to acetaminophen via ingestion of drinking water, and ingestion and dermal contact with this compound and other products containing
acetaminophen(SRC). Exposure to acetaminophen among the general population may be widespread through use of the drug as an analgesic(SRC).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available
from, as of Mar 6, 2014: http://www.cdc.gov/noes/
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 49/69
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Disease References
PubMed: 7482520, 19006102, 23940645, 24424155, 20156336, 19678709, 22148915, 25105552, 21773981,
25037050, 27015276, 27107423, 27275383, 28587349
Colorectal cancer Silke Matysik, Caroline Ivanne Le Roy, Gerhard Liebisch, Sandrine Paule Claus. Metabolomics of fecal
samples: A practical consideration. Trends in Food Science & Technology. Vol. 57, Part B, Nov. 2016, p.244-
255: http://www.sciencedirect.com/science/article/pii/S0924224416301984
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 50/69
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16 Literature
PubChem
PubChem
Springer Nature
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 51/69
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Thieme Chemistry
Wiley
PubChem
DrugBank
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6. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs:
cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31. Epub 2002 Sep 19. [PMID:12242329]
7. Adjei AA, Gaedigk A, Simon SD, Weinshilboum RM, Leeder JS: Interindividual variability in acetaminophen sulfation by human fetal liver: implications for pharmacogenetic investigations
of drug-induced birth defects. Birth Defects Res A Clin Mol Teratol. 2008 Mar;82(3):155-65. doi: 10.1002/bdra.20535. [PMID:18232020]
8. Hazai E, Vereczkey L, Monostory K: Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun. 2002 Mar 8;291(4):1089-94. [PMID:11866476]
9. Mazaleuskaya LL, Sangkuhl K, Thorn CF, FitzGerald GA, Altman RB, Klein TE: PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses.
Pharmacogenet Genomics. 2015 Aug;25(8):416-26. doi: 10.1097/FPC.0000000000000150. [PMID:26049587]
10. Ennis ZN, Dideriksen D, Vaegter HB, Handberg G, Pottegard A: Acetaminophen for Chronic Pain: A Systematic Review on Efficacy. Basic Clin Pharmacol Toxicol. 2016 Mar;118(3):184-9. doi:
10.1111/bcpt.12527. Epub 2015 Dec 28. [PMID:26572078]
11. Bannwarth B, Pehourcq F: [Pharmacologic basis for using paracetamol: pharmacokinetic and pharmacodynamic issues]. Drugs. 2003;63 Spec No 2:5-13. [PMID:14758786]
12. Forrest JA, Clements JA, Prescott LF: Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982 Mar-Apr;7(2):93-107. [PMID:7039926]
13. Ricciotti E, FitzGerald GA: Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011 May;31(5):986-1000. doi: 10.1161/ATVBAHA.110.207449. [PMID:21508345]
14. Valerie Gerriets; Thomas M. Nappe (2019). Acetaminophen. StatPearls publishing.
15. Acetaminophen tablet, DailyMed
16. Acetaminophen effervescent tablets, Cleveland Clinic
17. FDA safety communication: FDA has reviewed possible risks of pain medicine use during pregnancy
18. U.S. National Medical Library: MedlinePlus- Acetaminophen dosing for children
19. FDA consumer health information: Acetaminophen
20. FDA : Acetaminophen Information
21. Using Acetaminophen and Nonsteroidal Anti-inflammatory Drugs Safely
22. Acetaminophen FDA Label
DrugBank
PubChem
PubChem
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 53/69
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PubChem
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 54/69
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17 Patents
USRE39221 US8394408 US8741959
US5972916 US9050335
US6488962 US8658631
US6028222 US9399012
US6992218 US9610265
US8372432 US9468636
US8668929 US9132125
US8377453 US8828978
US7976870 US9549923
US8741885 US8748413
US8992975 US8461137
US8597681 US9987238
US8980319 US10383834
DrugBank
PubChem
PubChem
PATENTSCOPE (WIPO)
Patent 6992218
FDA Drugs
Patent 7976870
Drug Application N204031 (Prescription Drug: XARTEMIS XR. Ingredients: ACETAMINOPHEN | OXYCODONE HYDROCHLORIDE)
FDA Drugs
Patent 8372432
Drug Application N204031 (Prescription Drug: XARTEMIS XR. Ingredients: ACETAMINOPHEN | OXYCODONE HYDROCHLORIDE)
FDA Drugs
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 55/69
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PubChem
Action inhibitor
Specific Function
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 56/69
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Cytosolic prostaglandin synthase that catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) (PubMed:10922363). Molecular chaperone
that localizes to genomic response elements in a hormone-dependent manner and disrupts receptor-mediated transcriptional activation, by promoting disassembly of transcriptional
regulatory complexes (PubMed:11274138, PubMed:12077419). Facilitates HIF alpha proteins hydroxylation via interaction with EGLN1/PHD2, leading to recruit EGLN1/PHD2 to the
HSP90 pathway (PubMed:24711448).
1. Botting R, Ayoub SS: COX-3 and the mechanism of action of paracetamol/acetaminophen. Prostaglandins Leukot Essent Fatty Acids. 2005 Feb;72(2):85-7. [PMID:15626590]
Interaction References 2. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other
analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31. Epub 2002 Sep 19. [PMID:12242329]
DrugBank
DrugBank
DrugBank
18.7 Pathways
PubChem
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 57/69
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PubChem
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 58/69
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20 Classification
20.1 Ontologies
MeSH
ChEBI
KEGG
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 59/69
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KEGG
KEGG
KEGG
KEGG
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 60/69
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KEGG
KEGG
KEGG
KEGG
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 61/69
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WHO ATC
20.1.13 ChemIDplus
ChemIDplus
CAMEO Chemicals
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 62/69
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ChEMBL
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 63/69
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CCSBase
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 64/69
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21 Information Sources
FILTER BY SOURCE ALL SOURCES
1. CAMEO Chemicals
LICENSE
CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the
copyright restrictions of the companies or organizations that provided the data.
https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
4-HYDROXYACETANILIDE
https://cameochemicals.noaa.gov/chemical/20492
2. ChemIDplus
LICENSE
https://www.nlm.nih.gov/copyright.html
Acetaminophen [USP:JAN]
https://chem.nlm.nih.gov/chemidplus/sid/0000103902
ChemIDplus Chemical Information Classification
https://chem.nlm.nih.gov/chemidplus/
3. DrugBank
LICENSE
Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
https://www.drugbank.ca/legal/terms_of_use
Acetaminophen
http://www.drugbank.ca/drugs/DB00316
http://www.drugbank.ca/drugs/DB00316#targets
http://www.drugbank.ca/drugs/DB00316#enzymes
http://www.drugbank.ca/drugs/DB00316#transporters
http://www.drugbank.ca/drugs/DB00316#carriers
4. DTP/NCI
LICENSE
https://www.cancer.gov/policies/copyright-reuse
acetaminophen
https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=755853
acetaminophen
https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=109028
acetaminophen
https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=3991
Acetamide, N-(4-hydroxyphenyl)-
https://www.epa.gov/chemicals-under-tsca
6. EPA DSSTox
LICENSE
https://www.epa.gov/privacy/privacy-act-laws-policies-and-resources
Acetaminophen
https://comptox.epa.gov/dashboard/DTXSID2020006
Paracetamol
https://echa.europa.eu/substance-information/-/substanceinfo/100.002.870
Paracetamol
https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/82701
Acetaminophen
http://www.hmdb.ca/metabolites/HMDB0001859
PARACETAMOL
https://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1330
11. FooDB
LICENSE
FooDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material
(FooDB) and the original publication.
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 65/69
10/8/2020 Acetaminophen | C8H9NO2 - PubChem
https://foodb.ca/about
Acetaminophen
https://foodb.ca/compounds/FDB022713
12. ChEBI
Paracetamol
http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:46195
ChEBI Ontology
http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
Darvocet
https://www.deadiversion.usdoj.gov/schedules/
14. LiverTox
LICENSE
https://www.nlm.nih.gov/copyright.html
Acetaminophen
https://www.ncbi.nlm.nih.gov/books/n/livertox/Acetaminophen/
Acetaminophen
https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C198
17. CCSbase
Paracetamol
19. ClinicalTrials.gov
LICENSE
The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any
additional terms of use.
https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
https://clinicaltrials.gov/
http://ctdbase.org/detail.go?type=chem&acc=C083640
http://ctdbase.org/detail.go?type=chem&acc=D000082
21. DailyMed
LICENSE
https://www.nlm.nih.gov/copyright.html
ACETAMINOPHEN
https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=ACETAMINOPHEN
ACETAMINOPHEN; BUTALBITAL
https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=ACETAMINOPHEN;+BUTALBITAL
https://www.dgidb.org/drugs/ACETAMINOPHEN
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 66/69
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Ibuprofen, Paracetamol (P/0135/2018)
https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-002002-pip02-17
Paracetamol (P/96/2008)
https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/paracetamol
acetaminophen
https://comptox.epa.gov/dashboard/DTXSID2020006#exposure
https://ecotox.ipmcenters.org/
28. NITE-CMC
4'-Hydroxyacetanilide - FY2008
https://www.nite.go.jp/chem/english/ghs/08-meti-0051e.html
https://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
362O9ITL9D
https://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/
Acetaminophen
http://mona.fiehnlab.ucdavis.edu/spectra/browse?inchikey=RZVAJINKPMORJF-UHFFFAOYSA-N
32. SpectraBase
https://spectrabase.com/spectrum/F6VeaPs9sR6
https://spectrabase.com/spectrum/4Xu5pkRWXvV
https://spectrabase.com/spectrum/7xtzaWAUUBS
https://spectrabase.com/spectrum/K2PcvM9r7dk
https://spectrabase.com/spectrum/If1pbkFBWio
https://spectrabase.com/spectrum/CAhwsd7cimx
https://spectrabase.com/spectrum/1r5huGeSUfW
https://spectrabase.com/spectrum/CgjC8JPEboV
https://spectrabase.com/spectrum/67jwNuR3vBi
https://spectrabase.com/spectrum/JlsHb9oI8k8
https://spectrabase.com/spectrum/K4jDnDRRu4
https://spectrabase.com/spectrum/Ae3kpQprzn9
https://spectrabase.com/spectrum/JjpzPlSnRJD
https://spectrabase.com/spectrum/3IMZMOHylus
https://spectrabase.com/spectrum/Eo3dpxvlVBD
https://spectrabase.com/spectrum/JbST7y0eWIY
https://spectrabase.com/spectrum/53SvdHkrDNH
https://spectrabase.com/spectrum/Gw7FMQ8irYZ
https://spectrabase.com/spectrum/LCGABt4NVLs
https://spectrabase.com/spectrum/Lls4DOZ3vaa
https://spectrabase.com/spectrum/uvbq6dsvv3
https://spectrabase.com/spectrum/LClNFyR7sk4
https://spectrabase.com/spectrum/L8jWuA5EWW9
33. NMRShiftDB
https://pubchem.ncbi.nlm.nih.gov/substance/22388563
35. Wikipedia
acetaminophen
https://en.wikipedia.org/wiki/Acetaminophen
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 67/69
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38. PubChem
https://pubchem.ncbi.nlm.nih.gov
http://www.rcsb.org/ligand/TYL
41. SpringerMaterials
N-(4-hydroxyphenyl)ethanamide
https://materials.springer.com/substanceprofile/docs/smsid_smvbitdhzussqntj
43. The National Institute for Occupational Safety and Health (NIOSH)
LICENSE
The information provided using CDC Web site is only intended to be general summary information to the public. It is not intended to take the place of either the written law or regulations.
https://www.cdc.gov/Other/disclaimer.html
Acetanilide, 4'-hydroxy-
https://www.cdc.gov/niosh-rtecs/AE401640.html
https://www.whocc.no/atc/
46. Wiley
https://pubchem.ncbi.nlm.nih.gov/substance/?source=wiley&sourceid=117337
47. MeSH
Acetaminophen
https://www.ncbi.nlm.nih.gov/mesh/68000082
MeSH Tree
http://www.nlm.nih.gov/mesh/meshhome.html
Antipyretics
https://www.ncbi.nlm.nih.gov/mesh/68058633
Analgesics, Non-Narcotic
https://www.ncbi.nlm.nih.gov/mesh/68018712
48. KEGG
Carcinogens
http://www.genome.jp/kegg-bin/get_htext?br08008.keg
Drug Classes
http://www.genome.jp/kegg-bin/get_htext?br08330.keg
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 68/69
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51. ChEMBL
Target Tree
https://www.ebi.ac.uk/chembl/target/browser
53. CCSBase
CCSBase Classification
https://ccsbase.net/
55. NCBI
https://www.ncbi.nlm.nih.gov/projects/linkout
https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen 69/69