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Acetaminophen

PubChem CID
1983
Structure
Acetaminophen_small.png
Acetaminophen_3D_Structure.png
Acetaminophen__Crystal_Structure.png
Molecular Formula
Synonyms
  • acetaminophen
  • Paracetamol
  • 4-Acetamidophenol
  • 103-90-2
  • Tylenol
Molecular Weight
151.16 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2004-09-16
  • Modify:
    2025-01-11
Description
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.
Paracetamol is a member of the class of phenols that is 4-aminophenol in which one of the hydrogens attached to the amino group has been replaced by an acetyl group. It has a role as a cyclooxygenase 2 inhibitor, a cyclooxygenase 1 inhibitor, a non-narcotic analgesic, an antipyretic, a non-steroidal anti-inflammatory drug, a cyclooxygenase 3 inhibitor, a xenobiotic, an environmental contaminant, a human blood serum metabolite, a hepatotoxic agent, a ferroptosis inducer and a geroprotector. It is a member of phenols and a member of acetamides. It is functionally related to a 4-aminophenol.
Acetaminophen (paracetamol), also commonly known as Tylenol, is the most commonly taken analgesic worldwide and is recommended as first-line therapy in pain conditions by the World Health Organization (WHO). It is also used for its antipyretic effects, helping to reduce fever. This drug was initially approved by the U.S. FDA in 1951 and is available in a variety of forms including syrup form, regular tablets, effervescent tablets, injection, suppository, and other forms. Acetaminophen is often found combined with other drugs in more than 600 over the counter (OTC) allergy medications, cold medications, sleep medications, pain relievers, and other products. Confusion about dosing of this drug may be caused by the availability of different formulas, strengths, and dosage instructions for children of different ages. Due to the possibility of fatal overdose and liver failure associated with the incorrect use of acetaminophen, it is important to follow current and available national and manufacturer dosing guidelines while this drug is taken or prescribed.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Acetaminophen.png

1.2 3D Conformer

1.3 Crystal Structures

1 of 63
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CCDC Number
Crystal Structure Data
Crystal Structure Depiction
Crystal Structure Depiction

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-(4-hydroxyphenyl)acetamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

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 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RZVAJINKPMORJF-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC(=O)NC1=CC=C(C=C1)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C8H9NO2
Computed by PubChem 2.2 (PubChem release 2021.10.14)

C8H9NO2

HOC6H4NHCOCH3

2.3 Other Identifiers

2.3.1 CAS

103-90-2

2.3.2 Deprecated CAS

1430221-00-3, 719293-04-6, 8055-08-1
719293-04-6, 8055-08-1

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 ICSC Number

2.3.11 KEGG ID

2.3.12 Metabolomics Workbench ID

2.3.13 NCI Thesaurus Code

2.3.14 Nikkaji Number

2.3.15 NSC Number

2.3.16 PharmGKB ID

2.3.17 Pharos Ligand ID

2.3.18 RXCUI

2.3.19 Wikidata

2.3.20 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Acamol
  • Acephen
  • Acetaco
  • Acetamidophenol
  • Acetaminophen
  • Acetominophen
  • Algotropyl
  • Anacin 3
  • Anacin-3
  • Anacin3
  • APAP
  • Datril
  • Hydroxyacetanilide
  • N-(4-Hydroxyphenyl)acetanilide
  • N-Acetyl-p-aminophenol
  • p-Acetamidophenol
  • p-Hydroxyacetanilide
  • Panadol
  • Paracetamol
  • Tylenol

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
151.16 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
0.5
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
151.063328530 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
151.063328530 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
49.3 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
11
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
139
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

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.
Colorless solid; [ICSC] Odorless white solid; [CAMEO] White powder; [Sigma-Aldrich MSDS]
Solid
COLOURLESS CRYSTALS OR CRYSTALLINE POWDER.

3.2.2 Color / Form

Large monoclinic prisms from water
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10

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

Slightly bitter taste
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11

3.2.5 Boiling Point

>500
>500 °C

3.2.6 Melting Point

336 to 342 °F (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.
168-172
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
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
170 °C
169-170 °C

3.2.7 Solubility

>22.7 [ug/mL] (The mean of the results at pH 7.4)
1 to 5 mg/mL at 72 °F (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.
very slightly soluble in cold water but greater solubility in hot water
In water, 14,000 mg/L at 25 °C
Yalkowsky, S.H., He, Yan, Jain, P. Handbook of Aqueous Solubility Data Second Edition. CRC Press, Boca Raton, FL 2010, p. 492
Very slightly soluble in cold water, soluble in boiling water
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
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
Solubility in water, g/100ml at 20 °C: 1.4 (moderate)

3.2.8 Density

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

3.2.9 Vapor Density

Relative vapor density (air = 1): 5.2

3.2.10 Vapor Pressure

0.000007 [mmHg]
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

0.46
log Kow = 0.46
Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: https://logkow.cisti.nrc.ca/logkow/search.html
0.46
SANGSTER (1994)
0.49

3.2.12 Stability / Shelf Life

Stable under recommended storage conditions.
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: https://www.sigmaaldrich.com/safety-center.html

3.2.13 Autoignition Temperature

540 °C

3.2.14 pH

Saturated aqueous solution: 5.5-6.5
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11

3.2.15 Dissociation Constants

pKa = 9.38
Dastmalchi S et al; J Sch Pharm, Med Sci Univ Tehran 4: 7-14 (1995)

3.2.16 Collision Cross Section

129.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
132.2 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

131.43 Ų [M-H]-

130.56 Ų [M+H]+

S61 | UJICCSLIB | Collision Cross Section (CCS) Library from UJI | DOI:10.5281/zenodo.3549476

139.3 Ų [M+H]+

132.7 Ų [M-H]-

S50 | CCSCOMPEND | The Unified Collision Cross Section (CCS) Compendium | DOI:10.5281/zenodo.2658162

3.2.17 Kovats Retention Index

Standard non-polar
1668 , 1636 , 1631 , 1631 , 1632 , 1643 , 1650 , 1664 , 1678 , 1675.7 , 1694.6 , 1652.3 , 1631 , 1636 , 1687
Semi-standard non-polar
1694 , 1697 , 1703 , 1693.1

3.2.18 Other Experimental Properties

Decomposed by strong alkalies
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11

3.3 SpringerMaterials Properties

3.4 Chemical Classes

Other Uses -> Pharmaceuticals
Pharmaceutical

3.4.1 Drugs

Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> Analgesics
S56 | UOATARGPHARMA | Target Pharmaceutical/Drug List from University of Athens | DOI:10.5281/zenodo.3248837
Pharmaceutical
S120 | DUSTCT2024 | Substances from Second NORMAN Collaborative Dust Trial | DOI:10.5281/zenodo.13835254
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.4.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Analgesics, Non-Narcotic
Human drug -> Over-the-counter; Discontinued
Human drug -> Discontinued
Human drug -> Over-the-counter
Human drug -> Prescription; Over-the-counter; Discontinued; Active ingredient (ACETAMINOPHEN)
Paediatric drug
3.4.1.2 Animal Drugs
Pharmaceuticals -> Animal Drugs -> Approved in Taiwan
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664
Pharmaceuticals -> UK Veterinary Medicines Directorate List
S104 | UKVETMED | UK Veterinary Medicines Directorate's List | DOI:10.5281/zenodo.7802119

3.4.2 Cosmetics

Stabilizing
S13 | EUCOSMETICS | Combined Inventory of Ingredients Employed in Cosmetic Products (2000) and Revised Inventory (2006) | DOI:10.5281/zenodo.2624118

3.4.3 Endocrine Disruptors

Potential endocrine disrupting compound
S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2 | DOI:10.5281/zenodo.10944198

4 Spectral Information

4.1 1D NMR Spectra

1D NMR Spectra

4.1.1 1H NMR Spectra

1 of 4
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Spectra ID
Instrument Type
Varian
Frequency
500 MHz
Solvent
5%_DMSO
pH
7.00
Shifts [ppm]:Intensity
1.97:100.00, 9.11:34.80, 7.31:35.75, 6.65:35.56, 9.63:20.93, 6.67:40.69, 7.33:37.16
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Spectra ID
Instrument Type
JEOL
Frequency
400 MHz
Solvent
DMSO-d6
Shifts [ppm]:Intensity
1.99:1000.00, 9.66:101.00, 7.34:275.00, 7.36:85.00, 7.33:34.00, 6.70:91.00, 7.35:90.00, 6.68:271.00, 7.36:262.00, 7.37:24.00, 6.70:290.00, 6.68:86.00, 9.14:458.00, 6.67:32.00, 6.71:28.00
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4.1.2 13C NMR Spectra

1 of 3
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Spectra ID
Instrument Type
JEOL
Frequency
22.53 MHz
Solvent
DMSO-d6
Shifts [ppm]:Intensity
130.99:295.00, 114.97:1000.00, 23.61:250.00, 167.44:188.00, 153.15:256.00, 120.91:480.00
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Source of Sample
MCB Manufacturing Chemists, Norwood, Ohio
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.1.3 15N NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.1.4 17O NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 2D NMR Spectra

4.2.1 1H-13C NMR Spectra

2D NMR Spectra Type
1H-13C HSQC
Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
Water
pH
7.00
Shifts [ppm] (F2:F1):Intensity
7.23:127.38:0.63, 6.89:118.43:0.52, 2.13:25.22:1.00
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4.3 Mass Spectrometry

4.3.1 GC-MS

1 of 16
View All
Spectra ID
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

109.0 99.99

151.0 34.59

80.0 9.49

110.0 7.64

108.0 7.14

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Notes
instrument=HITACHI M-80
2 of 16
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Spectra ID
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

109.0 99.99

151.0 26.90

79.0 19.30

80.0 12.90

53.0 10.70

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Notes
instrument=Unknown

4.3.2 MS-MS

1 of 9
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Spectra ID
Instrument Type
Quattro_QQQ
Ionization Mode
Positive
Top 5 Peaks

152.349 100

109.615 81.87

111.118 68.32

111.745 66.47

151.471 56.21

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Notes
delivery=Flow_Injectionanalyzer=Triple_Quad
2 of 9
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Spectra ID
Instrument Type
Quattro_QQQ
Ionization Mode
Positive
Top 5 Peaks

110.492 100

110.617 88.08

152.098 62.75

152.599 38.30

151.471 37.88

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Notes
delivery=Flow_Injectionanalyzer=Triple_Quad

4.3.3 LC-MS

1 of 84
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Authors
ACESx, Jonathan W. Martin Group
Instrument
QExactive Orbitrap HF-X (Thermo Scientific)
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
Ramp 20%-70% (nominal)
Fragmentation Mode
HCD
Column Name
Waters; Acquity UPLC BEH C18, 2.1 x 100 mm, 1.7 um, Waters
Retention Time
6.4518
Top 5 Peaks

152.0708 999

110.06029 939

93.03372 112

92.04984 65

65.03873 61

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License
CC BY
2 of 84
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Authors
ACESx, Jonathan W. Martin Group
Instrument
QExactive Orbitrap HF-X (Thermo Scientific)
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
NEGATIVE
Ionization
ESI
Collision Energy
Ramp 20%-70% (nominal)
Fragmentation Mode
HCD
Column Name
Waters; Acquity UPLC BEH C18, 2.1 x 100 mm, 1.7 um, Waters
Retention Time
6.3002
Precursor m/z
150.0563
Top 5 Peaks

150.05621 999

107.03799 663

108.0463 43

108.04523 39

132.04579 14

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License
CC BY

4.3.4 Other MS

1 of 8
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Other MS
MASS: 4765 (NIST/EPA/MSDC Mass Spectral database, 1990 version)
2 of 8
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Authors
HASHIMOTO K, KYOTO COLLEGE OF PHARMACY
Instrument
HITACHI M-80
Instrument Type
EI-B
MS Level
MS
Ionization Mode
POSITIVE
Ionization
ENERGY 20 eV
Top 5 Peaks

109 999

151 346

80 95

110 76

108 71

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License
CC BY-NC-SA

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
UV: 2913 (Sadtler Research Laboratories spectral collection)
Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 58

4.5 IR Spectra

IR Spectra
IR: 5420 (Coblentz Society spectral collection)

4.5.1 FTIR Spectra

1 of 2
Technique
KBr WAFER
Source of Sample
S. B. Penick & Company
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Instrument Name
Bruker IFS 85
Technique
KBr-Pellet
Copyright
Copyright © 1989, 1990-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
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4.5.2 ATR-IR Spectra

1 of 2
Instrument Name
Bio-Rad FTS
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Sigma-Aldrich Inc.
Catalog Number
A7085
Lot Number
099K0126
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Instrument Name
Bruker Tensor 27 FT-IR
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Bio-Rad Laboratories, Inc.
Source of Sample
Sigma Aldrich Company Llc.
Catalog Number
A5000
Copyright
Copyright © 2016-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.6 Raman Spectra

1 of 3
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Raman Spectra
Raman: 930 (Sadtler Research Laboratories spectral collection)
2 of 3
View All
Technique
FT-Raman
Source of Spectrum
Forensic Spectral Research
Source of Sample
Sigma-Aldrich Inc.
Catalog Number
A7085
Lot Number
099K0126
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.7 Other Spectra

Intense mass spectral peaks: 80 m/z, 109 m/z, 151 m/z
Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985., p. 206

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

In general, acetaminophen is used for the treatment of mild to moderate pain and reduction of fever. 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. 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. Specific dosing guidelines should be followed when administering acetaminophen to children.
Moderate pain and fever

7.2 LiverTox Summary

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.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Analgesics, Non-Narcotic
Nonsteroidal Antiinflammatory Drugs

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 Drug Labels

Drug and label
Active ingredient and drug

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.8.3 NIPH Clinical Trials Search of Japan

7.9 EMA Drug Information

Type
Paediatric investigation
Active Substance
Therapeutic Area
Pain
Drug Form
Solution for infusion
Administration Route
Intravenous use
Decision Type
P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s)
Decision Date
2008-11-03

7.10 Therapeutic Uses

Analgesics, Non-Narcotic; Antipyretics
National Library of Medicine's Medical Subject Headings. Acetaminophen. Online file (MeSH, 2014). Available from, as of January 30, 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html
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: https://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
For more Therapeutic Uses (Complete) data for ACETAMINOPHEN (11 total), please visit the HSDB record page.

7.11 Drug Warnings

The U.S. Food and Drug Administration (FDA) is informing the public that acetaminophen has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal. Acetaminophen is a common active ingredient to treat pain and reduce fever; it is included in many prescription and over-the-counter (OTC) products. Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain acetaminophen. These reactions can occur with first-time use of acetaminophen or at any time while it is being taken. ... Anyone who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away. Anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers. Health care professionals 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: https://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: https://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: https://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: https://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.

7.12 Reported Fatal Dose

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
25 g for an adult human. (A308)
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

7.13 Drug Tolerance

Although psychologic dependence on acetaminophen may occur, tolerance and physical dependence do not appear to develop even with prolonged use.
Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 2181

8 Agrochemical Information

8.1 Agrochemical Category

Special Use

9 Pharmacology and Biochemistry

9.1 Pharmacodynamics

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

9.2 MeSH Pharmacological Classification

Antipyretics
Drugs that are used to reduce body temperature in fever. (See all compounds classified as Antipyretics.)
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.)

9.3 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

N - Nervous system

N02 - Analgesics

N02B - Other analgesics and antipyretics

N02BE - Anilides

N02BE01 - Paracetamol

9.4 Absorption, Distribution and Excretion

Absorption
Acetaminophen has 88% oral bioavailability and reaches its highest plasma concentration 90 minutes after ingestion. Peak blood levels of free acetaminophen are not reached until 3 hours after rectal administration of the suppository form of acetaminophen and the peak blood concentration is approximately 50% of the observed concentration after the ingestion of an equivalent oral dose (10-20 mcg/mL). The percentage of a systemically absorbed rectal dose of acetaminophen is inconsistent, demonstrated by major differences in the bioavailability of acetaminophen after a dose administered rectally. Higher rectal doses or an increased frequency of administration may be used to attain blood concentrations of acetaminophen similar to those attained after oral acetaminophen administration.
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.
Volume of Distribution
Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat.
Clearance
Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).
Acetaminophen is rapidly and almost completely absorbed from the GI tract following oral administration. In healthy men, steady-state oral bioavailability of 1.3-g doses of extended-release tablets of acetaminophen administered every 8 hours for a total of 7 doses was equal to 1-g doses of conventional tablets of acetaminophen given every 6 hours for a total of 7 doses. Food may delay slightly absorption of extended-release tablets of acetaminophen. Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentrations are attained within 10-60 or 60-120 minutes, respectively. Following oral administration of a single 500-mg conventional tablet or a single 650-mg extended-release tablet, average plasma acetaminophen concentrations of 2.1 or 1.8 ug/mL, respectively, occur at 6 or 8 hours, respectively. In addition, dissolution of the extended-release tablets may depend slightly on the gastric or intestinal pH. Dissolution appears to be slightly faster in the alkaline pH of the intestines compared with the acidic pH of the stomach; however, this is of no clinical importance. Following administration of conventional preparations of acetaminophen, only small amounts of the drug are detectable in plasma after 8 hours. The extended-release tablets of acetaminophen release the drug for up to 8 hours, but in vitro data indicate that at least 95% of the dose is released within 5 hours.
American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
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.

9.5 Metabolism / Metabolites

Acetaminophen is the major metabolite of _phenacetin_ and _acetanilid_. Acetaminophen is mainly metabolized in the liver by first-order kinetics and its metabolism of comprised of 3 pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation through the cytochrome P450 enzyme pathway, mainly CYP2E1, to produce a reactive metabolite (N-acetyl-p-benzoquinone imine or NAPQI). At normal therapeutic doses, NAPQI undergoes fast conjugation with glutathione and is subsequently metabolized to produce both cysteine and mercapturic acid conjugates. High doses of acetaminophen (overdoses) can lead to hepatic necrosis due to the depletion of glutathione and of binding of high levels of reactive metabolite (NAPQI) to important parts of liver cells. The abovementioned damage to the liver can be prevented by the early administration of sulfhydryl compounds, for example, methionine and N-acetylcysteine.
About 80-85% of the acetaminophen in the body undergoes conjugation principally with glucuronic acid and to a lesser extent with sulfuric acid. Acetaminophen also is metabolized by microsomal enzyme systems in the liver.
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
For more Metabolism/Metabolites (Complete) data for ACETAMINOPHEN (7 total), please visit the HSDB record page.

Acetaminophen has known human metabolites that include 3-Hydroxyacetaminophen, N-Acetyl-p-benzoquinone, (2S,3S,4S,5R)-6-(4-Acetamidophenoxy)-3,4,5-trihydroxyoxane-2-carboxylic acid, and Acetaminophen sulfate.

Acetaminophen is a known human metabolite of phenacetin, p-Methoxyacetanilide, acetanilide, and O-isopropyl acetaminophen.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Acetaminophen primarily undergoes glucuronidation (45-55% of the dose) in which this process is facilitated by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver or UGT1A10 in the gut. 30-35% of the dose undergoes sulfation. This biotransformation is facilitated by SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. A small percentage of acetaminophen is oxidized by CYP2E1 to form N-acetyl-p-benzo-quinone imine (NAPQI), a toxic metabolite which is then conjugated to glutathione and excreted renally. Studies suggest that CYP3A4 and CYP2E1 are the primary cytochrome P450 isozymes responsible for the generation of toxic metabolites. Accumulation of NAPQI may occur if primary metabolic pathways are saturated. Acetaminophen is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion is metabolized via the hepatic cytochrome P450 enzyme system. The toxic effects of acetaminophen are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine), not acetaminophen itself nor any of the major metabolites. This toxic metabolite reacts with sulfhydryl groups. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys. The toxic dose of paracetamol is highly variable. Route of Elimination: Approximately 80% of acetaminophen is excreted in the urine after conjugation and about 3% is excreted unchanged. Half Life: 1 to 4 hours

9.6 Biological Half-Life

The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen.
The elimination half life is 1-3 hours after a therapeutic dose but may be greater than 12 hours after an overdose.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69

9.7 Mechanism of Action

According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (nonsteroidal anti-inflammatory drugs) due to its ability to inhibit the cyclooxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms. One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclooxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as _COX-3_. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge.
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.
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.
Karadas S et al; Hum Exp Toxicol 33 (11): 1134-40 (2014)
For more Mechanism of Action (Complete) data for ACETAMINOPHEN (9 total), please visit the HSDB record page.

9.8 Human Metabolite Information

9.8.1 Tissue Locations

  • All Tissues
  • Placenta

9.8.2 Cellular Locations

Cytoplasm

9.8.3 Metabolite Pathways

9.9 Biochemical Reactions

9.10 Transformations

10 Use and Manufacturing

10.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
Sources/Uses
Registered for use in the US for control of brown tree snakes; [NPIRS] Used to make azo dyes, photographic chemicals, and pharmaceuticals, as a stabilizer for hydrogen peroxide, and as a therapeutic analgesic and antipyretic; [HSDB]
Manufacture of azo dyes, photographic chemicals.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
Stabilizer for hydrogen peroxide
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11
An analgesic used as an aspirin substitute
Nugent RA, Hall CM; Analgesics, Antipyrenes, and Antiinflammatory Agents. Kirk-Othmer Encyclopedia of Chemical Technology. (1999-2014). New York, NY: John Wiley & Sons. Online Posting Date: 4 Dec 2000
Analgesics, Non-Narcotic; Antipyretics
National Library of Medicine's Medical Subject Headings. Acetaminophen. Online file (MeSH, 2014). Available from, as of January 30, 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html
For more Uses (Complete) data for ACETAMINOPHEN (6 total), please visit the HSDB record page.

Use (kg) in Switzerland (2009): >100000

Use (kg; approx.) in Germany (2009): >500000

Use (kg; exact) in Germany (2009): 564712

Use (kg) in USA (2002): 5790000

Use (kg) in France (2004): 3303077

Consumption (g per capita) in Switzerland (2009): 13

Consumption (g per capita; approx.) in Germany (2009): 6.1

Consumption (g per capita; exact) in Germany (2009): 6.9

Consumption (g per capita) in the USA (2002): 21

Consumption (g per capita) in France (2004): 55

Excretion rate: 0.037

Calculated removal (%): 75.1

An over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies.

10.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
Cosmetics -> Stabilizing
S13 | EUCOSMETICS | Combined Inventory of Ingredients Employed in Cosmetic Products (2000) and Revised Inventory (2006) | DOI:10.5281/zenodo.2624118
Pharmaceuticals -> Animal Drugs -> Approved in Taiwan
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

10.2 Methods of Manufacturing

p-Nitrophenol is reduced and the resulting p-aminophenol is acetylated by means of heating with a mixture of acetic anhydride and glacial acetic acid. The crude product may be purified by recrystallization from an ethanol-water mixture.
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1541
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
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

10.3 Formulations / Preparations

Table: Acetaminophen Preparations
Route of Administration
Oral
Dosage Form
Capsules
Strength
500 mg
Brand or Generic Name (Manufacturer)
Acetaminophen Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Solution
Strength
167 mg/5 mL
Brand or Generic Name (Manufacturer)
Tylenol Extra-Strength Adult (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Solution
Strength
100 mg/mL
Brand or Generic Name (Manufacturer)
Tylenol Concentrated Drops Infant's (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Suspension
Strength
160 mg/5 mL
Brand or Generic Name (Manufacturer)
Tylenol Oral Suspension Chilcren's (McNeil)
Route of Administration
Oral
Dosage Form
Suspension
Strength
160 mg/5 mL
Brand or Generic Name (Manufacturer)
Tylenol Oral Suspension Infant's (McNeil)
Route of Administration
Oral
Dosage Form
Tablets
Strength
325 mg
Brand or Generic Name (Manufacturer)
Tylenol Regular Strength, scored (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
500 mg
Brand or Generic Name (Manufacturer)
Tylenol Extra-Strength Rapid Release Gelcaps (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, extended-release, film coated
Strength
650 mg
Brand or Generic Name (Manufacturer)
Tylenol Arthritis Pain Extended Relief Caplets (McNeil)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
500 mg
Brand or Generic Name (Manufacturer)
Anacin Aspirin Free Extra Strength caplets (Insight) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
500 mg
Brand or Generic Name (Manufacturer)
Tylenol Extra Strength Caplets (McNeil)
Route of Administration
Oral
Dosage Form
Tablets, orally disintegrating
Strength
80 mg
Brand or Generic Name (Manufacturer)
Tylenol Meltaways Children's (McNeil)
Route of Administration
Oral
Dosage Form
Tablets, orally disintegrating
Strength
160 mg
Brand or Generic Name (Manufacturer)
Tylenol Meltaways Junior Strength (McNeil)
Route of Administration
Rectal
Dosage Form
Suppositories
Strength
80 mg
Brand or Generic Name (Manufacturer)
FeverAll Infants' (Alpharma)
Route of Administration
Rectal
Dosage Form
Suppositories
Strength
120 mg
Brand or Generic Name (Manufacturer)
Acephen (G&amp;W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Rectal
Dosage Form
Suppositories
Strength
120 mg
Brand or Generic Name (Manufacturer)
FeverAll Children's (Alpharma)
Route of Administration
Rectal
Dosage Form
Suppositories
Strength
125 mg
Brand or Generic Name (Manufacturer)
Acetaminophen Suppositories Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Rectal
Dosage Form
Suppositories
Strength
325 mg
Brand or Generic Name (Manufacturer)
Acephen (G&amp;W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Rectal
Dosage Form
Suppositories
Strength
325 mg
Brand or Generic Name (Manufacturer)
FeverAll Junior Strength (Alpharma)
Route of Administration
Rectal
Dosage Form
Suppositories
Strength
650 mg
Brand or Generic Name (Manufacturer)
Acephen (G&amp;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
Ofirmev: (acetaminophen) injection: 1000 mg/100mL (10 mg/mL)
US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
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
Proprietary Preparation: Crocin (India)
SWEETMAN, S.C. (ed.) Martindale-The Complete Drug Reference. 36th ed. London: The Pharmaceutical Press, 2009., p. 111

10.4 Consumption Patterns

PRINCIPALLY USED AS A MEDICINAL (1976).
SRI
Acetaminophen. Analgesic, 75%; exports, 25%.
Kavaler AR; Chemical Marketing Reporter 234 (25): 50 (1988)
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)

10.5 U.S. Production

(1975) 4.5X10+9 GRAMS (INCL PHENACETIN)
SRI
(1976) GREATER THAN 2.27X10+6 GRAMS
SRI
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.
Year
1986
Production Range (pounds)
10 thousand - 500 thousand
Year
1990
Production Range (pounds)
No Reports
Year
1994
Production Range (pounds)
>500 thousand - 1 million
Year
1998
Production Range (pounds)
10 thousand - 500 thousand
Year
2002
Production Range (pounds)
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: https://epa.gov/cdr/tools/data/2002-vol.html
For more U.S. Production (Complete) data for ACETAMINOPHEN (6 total), please visit the HSDB record page.

10.6 U.S. Imports

(1972) 9.1X10+7 GRAMS (PRINCPL CUSTMS DISTS)
SRI
(1975) 3.46X10+8 GRAMS (PRINCPL CUSTMS DISTS)
SRI

10.7 General Manufacturing Information

EPA TSCA Commercial Activity Status
Acetamide, N-(4-hydroxyphenyl)-: ACTIVE

11 Identification

11.1 Analytic Laboratory Methods

High performance liquid chromatography analysis of acetaminophen with UV detector. Flow rate is 215 mL/min, wavelength is 254 nm fixed or 250 nm variable.
Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975., p. 104
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.

11.2 Clinical Laboratory Methods

An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained by this device are used in the diagnosis and treatment of acetaminophen overdose.
21 CFR 862.3030 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 4, 2014: https://www.ecfr.gov/cgi-bin/ECFR?page=browse
Urine, colorimetry; chromatography, gas-liquid.
Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975., p. 13
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.
Pang KS et al; J Chromatogr 174 (1): 165 (1979)
Determination of phenacetin in blood plasma of animals by gas chromatography.
Kyo Y, Niwa H; Tohoku Yakka Daigaku Kenkyu Nempo 25: 71 (1978)
For more Clinical Laboratory Methods (Complete) data for ACETAMINOPHEN (8 total), please visit the HSDB record page.

12 Safety and Hazards

12.1 Hazards Identification

12.1.1 GHS Classification

1 of 4
View All
Note
Pictograms displayed are for 98.8% (408 of 413) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 1.2% (5 of 413) of reports.
Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements

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

H315 (18.2%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (17.9%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H412 (38.5%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P264, P264+P265, P270, P273, P280, P301+P317, P302+P352, P305+P351+P338, P321, P330, P332+P317, P337+P317, P362+P364, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 413 reports by companies from 47 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria per 5 of 413 reports by companies. For more detailed information, please visit ECHA C&L website.

There are 45 notifications provided by 408 of 413 reports by companies with hazard statement code(s).

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.

12.1.2 Hazard Classes and Categories

Acute Tox. 4 (98.1%)

Skin Irrit. 2 (18.2%)

Eye Irrit. 2 (17.9%)

Aquatic Chronic 3 (38.5%)

Hazardous to the aquatic environment (Acute) - Category 2

Hazardous to the aquatic environment (Long-term) - Category 2

12.1.3 Health Hazards

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.

12.1.4 Fire Hazards

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.
Combustible.

12.1.5 Hazards Summary

Ingestion may cause injury to the liver and kidneys; [ICSC] Histopathological changes of the liver, kidney, reproductive organs, thymus, and lymph nodes observed in 13-week feeding study of rats at 25,000 ppm; No evidence of carcinogenicity in male rats, male mice, or female mice; Equivocal evidence in female rats; [NTP] High oral doses produce testicular toxicity in rats and impaired spermiogenesis and testicular atrophy in mice and rats; [REPROTOX] A skin and strong eye irritant; Harmful by ingestion; Targets the liver and kidney; [Sigma-Aldrich MSDS]
REPROTOX - Scialli AR, Lione A, Boyle Padgett GK. Reproductive Effects of Chemical, Physical, and Biological Agents. Baltimore: The Johns Hopkins University Press, 1995.

12.1.6 Fire Potential

Not flammable or combustible.
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: https://www.sigmaaldrich.com/safety-center.html

12.2 Safety and Hazard Properties

12.2.1 Explosive Limits and Potential

Explosive limits , vol% in air: 15 - ?

12.3 First Aid Measures

Inhalation First Aid
Fresh air, rest.
Skin First Aid
Rinse and then wash skin with water and soap.
Eye First Aid
Rinse with plenty of water (remove contact lenses if easily possible).
Ingestion First Aid
Give one or two glasses of water to drink.

12.3.1 First Aid

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.

12.4 Fire Fighting

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

12.4.1 Fire Fighting Procedures

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: https://www.sigmaaldrich.com/safety-center.html

12.5 Accidental Release Measures

12.5.1 Spillage Disposal

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.

12.5.2 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: https://www.sigmaaldrich.com/safety-center.html

12.5.3 Disposal Methods

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: https://www.sigmaaldrich.com/safety-center.html

12.5.4 Preventive Measures

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: https://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: https://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: https://www.sigmaaldrich.com/safety-center.html

12.6 Handling and Storage

12.6.1 Nonfire Spill Response

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.

12.6.2 Safe Storage

Provision to contain effluent from fire extinguishing. Store in an area without drain or sewer access.

12.6.3 Storage Conditions

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: https://www.sigmaaldrich.com/safety-center.html
Ofirmev should be stored at 20 °C to 25 °C (68 °F to 77 °F). ... Do not refrigerate or freeze.
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
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

12.7 Exposure Control and Personal Protection

12.7.1 Inhalation Risk

A nuisance-causing concentration of airborne particles can be reached quickly.

12.7.2 Effects of Long Term Exposure

Ingestion may cause effects on the kidneys and liver. This may result in impaired functions.

12.7.3 Personal Protective Equipment (PPE)

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.
Hand protection: Handle with gloves.
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: https://www.sigmaaldrich.com/safety-center.html
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: https://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: https://www.sigmaaldrich.com/safety-center.html

12.7.4 Preventions

Fire Prevention
NO open flames.
Exposure Prevention
PREVENT DISPERSION OF DUST!
Inhalation Prevention
Use local exhaust or breathing protection.
Skin Prevention
Protective gloves.
Eye Prevention
Wear safety goggles.
Ingestion Prevention
Do not eat, drink, or smoke during work.

12.8 Stability and Reactivity

12.8.1 Air and Water Reactions

Slightly soluble in water.

12.8.2 Reactive Group

Amides and Imides

Phenols and Cresols

12.8.3 Reactivity Profile

4-HYDROXYACETANILIDE is sensitive to light. Incompatible with strong oxidizers. (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.

12.8.4 Hazardous Reactivities and Incompatibilities

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: https://www.sigmaaldrich.com/safety-center.html

12.9 Regulatory Information

The Australian Inventory of Industrial Chemicals
Chemical: Acetamide, N-(4-hydroxyphenyl)-
REACH Registered Substance
New Zealand EPA Inventory of Chemical Status
Paracetamol (4-hydroxyacetanilide): Does not have an individual approval but may be used under an appropriate group standard

12.9.1 FDA Requirements

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: https://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: https://www.fda.gov/cder/ob/

12.10 Other Safety Information

Chemical Assessment

IMAP assessments - Acetamide, N-(4-hydroxyphenyl)-: Environment tier I assessment

IMAP assessments - Acetamide, N-(4-hydroxyphenyl)-: Human health tier I assessment

12.10.1 Toxic Combustion Products

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: https://www.sigmaaldrich.com/safety-center.html

12.10.2 Special Reports

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]

13 Toxicity

13.1 Toxicological Information

13.1.1 Toxicity Summary

IDENTIFICATION AND USE: Acetaminophen is an odorless compound with a slightly bitter taste. It is a common analgesic and antipyretic agent used for the relief of fever as well as aches and pains associated with many conditions. HUMAN EXPOSURE AND TOXICITY: Nausea, vomiting, and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses of the drug. In severe poisoning, CNS stimulation, excitement, and delirium may occur initially. This may be followed by CNS depression, stupor, hypothermia, marked prostration, rapid shallow breathing, rapid weak irregular pulse, low blood pressure, and circulatory failure. When an individual has ingested a toxic dose of acetaminophen, the individual should be hospitalized for several days of observation, even if there are no apparent ill effects, because maximum liver damage and/or cardiotoxic effects usually do not become apparent until 2-4 days after ingestion of the drug. Other symptoms of acute poisoning include cerebral edema and nonspecific myocardial depression. Vascular collapse results from the relative hypoxia and from a central depressant action that occurs only with massive doses. Shock may develop if vasodilation is marked. Fatal seizures may occur. Coma usually precedes death, which may occur suddenly or may be delayed for several days. Biopsy of the liver reveals centralobular necrosis with sparing of the periportal area. There have been reports of acute myocardial necrosis and pericarditis in individuals with acetaminophen poisoning. Hypoglycemia, which can progress to coma have been reported in patients ingesting toxic doses of acetaminophen. Low prothrombin levels and thrombocytopenia have been reported in patients with acetaminophen poisoning. Skin reactions of an erythematous or urticarial nature which may be accompanied by fever and oral mucosal lesions also have been reported. For use anytime during pregnancy, 781 exposures were recorded, and possible associations with congenital dislocation of the hip (eight cases) and clubfoot (six cases) were found. There is inadequate evidence in humans for the carcinogenicity of acetaminophen. ANIMAL TOXICITY STUDIES: There is inadequate evidence in experimental animals for the carcinogenicity of acetaminophen. In rats fasted 24 hours and given a single dose of acetaminophen (2 g/kg) by gavage, liver necrosis around the central vein was noted at 9-12 hours and was much more extensive at 24 hours after treatment. In mice after dietary exposure to acetaminophen up to 6400 mg/kg daily for 13 weeks hepatotoxicity, organ weight changes and deaths were observed. Cats are particularly susceptible to acetaminophen intoxication, developing more diffuse liver changes, while hepatic centrilobular lesions found in dogs. High doses of acetaminophen caused testicular atrophy and delay in spermiogenesis in mice. Furthermore, reductions in the fertility and neonatal survival in mice were seen in the F0 generation and decreases in F1 pup weights were found at acetaminophen dose 1430 mg/kg. Acetaminophen was not mutagenic in Salmonella typhimurium assay with or without metabolic activation in six strains: TA1535, TA1537, TA1538, TA100, TA97 and TA98. In vitro and animal data indicate that small quantities of acetaminophen are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis in cases of overdose. Excipients found in liquid formulations of acetaminophen may decrease its liver toxicity. ECOTOXICITY STUDIES: Daphnia magna was the most susceptible among the test organisms to the environmental effects of acetaminophen. Acetaminophen has recently been identified as a promising snake toxicant to reduce brown tree snake populations on Guam, while posing only the minimal risks to non-target rodents, cats, pigs and birds.
Paracetamol toxicity is one of the most common causes of poisoning worldwide. The toxic effects of acetaminophen are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine – also known as NAPQI), not acetaminophen itself nor any of the other major metabolites. Cytochromes P450 2E1 and 3A4 convert approximately 5% of paracetamol to NAPQI. This toxic metabolite reacts with sulfhydryl groups on proteins and with glutathione (GSH). NAPQI depletes the liver's natural antioxidant glutathione and directly damages cells in the liver, leading to liver failure. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs. More specifically, oxidation by NAPQI of GSH to GSSG (oxidized glutathione) and the reduction of GSSG back to GSH by the NADPH-dependent glutathione reductase appear to be responsible for the rapid oxidation of NADPH that occurs in hepatocytes incubated with NAPQI. Risk factors for toxicity include excessive chronic alcohol intake, fasting or anorexia nervosa, and the use of certain drugs such as isoniazid. At usual doses, paracetamol is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys. The toxic dose of paracetamol is highly variable.

13.1.2 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Acetaminophen
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

13.1.3 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).

13.1.4 Drug Induced Liver Injury

Compound
acetaminophen
DILI Annotation
Most-DILI-Concern
Severity Grade
5
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

13.1.5 Evidence for Carcinogenicity

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: https://monographs.iarc.fr/ENG/Classification/index.php, p. 73 438 (1999)

13.1.6 Carcinogen Classification

1 of 3
IARC Carcinogenic Agent
Paracetamol (Acetaminophen)
IARC Carcinogenic Classes
Group 3: Not classifiable as to its carcinogenicity to humans
IARC Monographs

Volume 50: (1990) Pharmaceutical Drugs

Volume 73: (1999) Some Chemicals that Cause Tumours of the Kidney or Urinary Bladder in Rodents and Some Other Substances

2 of 3
NTP Technical Report
TR-394: Toxicology and Carcinogenesis Studies of Acetaminophen (CASRN 103-90-2) in F344/N Rats and B6C3F1 Mice (Feed Studies) (1993 )
Peer Review Date
Conclusion for Male Rat
No Evidence No Evidence
Conclusion for Female Rat
Equivocal Evidence Equivocal Evidence
Conclusion for Male Mice
No Evidence No Evidence
Conclusion for Female Mice
No Evidence No Evidence
Summary

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.

3 of 3
Carcinogen Classification
3, not classifiable as to its carcinogenicity to humans. (L135)

13.1.7 Health Effects

Skin rashes, blood disorders and a swollen pancreas have occasionally happened in people taking the drug on a regular basis for a long time.

13.1.8 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Acetaminophen is a good choice for analgesia, and fever reduction in nursing mothers. Giving acetaminophen and ibuprofen on a fixed schedule for 24 hours after vaginal delivery appears to increase the breastfeeding rate. There is no difference in breastfeeding initiation rate between ibuprofen or acetaminophen alone after vaginal delivery. Amounts in milk are much less than doses usually given to infants. Adverse effects in breastfed infants appear to be rare.

◉ Effects in Breastfed Infants

A maculopapular rash on the upper trunk and face of a 2-month-old infant was probably caused by acetaminophen in breastmilk. The rash occurred after 2 days of therapy in the mother at a dose of 1 gram at bedtime. It subsided when the drug was discontinued and recurred 2 weeks later after another acetaminophen dose of 1 gram was taken by the mother.

Two papers report 14 women who breastfed after taking acetaminophen or its prodrug phenacetin with no adverse effects to their infants.

In a telephone follow-up study, mothers reported no side effects among 43 infants exposed to acetaminophen in breastmilk.

Two clinicians speculated that breastmilk exposure to acetaminophen during breastfeeding might be a risk factor for asthma and wheezing in the breastfed infants based on their personal observations. However, these observations were uncontrolled and cannot be considered to be valid proof of an association.

◉ Effects on Lactation and Breastmilk

A randomized study compared the use of ibuprofen 400 mg plus acetaminophen 1 gram every 6 hours for 24 hours to the same combination on demand after normal vaginal delivery. Women who received the analgesics on a fixed schedule were more likely to breastfeed their baby (98% vs 88%) than those receiving analgesics on demand, even though their average pain scores were not different.

A double-blind study compared acetaminophen 1000 mg to ibuprofen for pain control after vaginal delivery. No difference was seen between the two treatments in the percentage of mothers who initiated breastfeeding of their infants.

13.1.9 Exposure Routes

The substance can be absorbed into the body by ingestion.
Oral, rapid and almost complete.

13.1.10 Symptoms

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

13.1.11 Adverse Effects

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

13.1.12 Acute Effects

13.1.13 Toxicity Data

LD50: 338 mg/kg (Oral, Mouse) (A308) LD50: 1944 mg/kg (Oral, Rat) (A308) In adults, single doses above 10 grams or 200 mg/kg of bodyweight, whichever is lower, have a reasonable likelihood of causing toxicity.
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

13.1.14 Treatment

In adults, the initial treatment for paracetamol overdose is gastrointestinal decontamination. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe. Gastric lavage, better known as stomach pumping, may be considered if the amount ingested is potentially life-threatening and the procedure can be performed within 60 minutes of ingestion. Acetylcysteine, when used early in the course of treatment, reduces morbidity and virtually eliminating mortality associated with even a massive acetaminophen overdose. (L1712) In patients who develop fulminant hepatic failure or who are otherwise expected to die from liver failure, the mainstay of management is liver transplantation.
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

13.1.15 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.

13.1.16 Antidote and Emergency Treatment

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
For more Antidote and Emergency Treatment (Complete) data for ACETAMINOPHEN (11 total), please visit the HSDB record page.

13.1.17 Human Toxicity Excerpts

/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.
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.
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.

13.1.18 Non-Human Toxicity Excerpts

/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.
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.
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.

13.1.19 Human Toxicity Values

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

13.1.20 Non-Human Toxicity Values

LD50 Rat oral 2400 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
LD50 Rat ip 1205 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
LD50 Mouse oral 338 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
LD50 Mouse ip 367 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
LD50 Mouse sc 310 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994

13.1.21 Ongoing Test Status

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]

13.1.22 National Toxicology Program Studies

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: https://ntp.niehs.nih.gov/index.cfm?objectid=0847F35A-0850-D1E7-B02ED4DDD150F990

13.1.23 Populations at Special Risk

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: https://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
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.
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: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7

13.1.24 Protein Binding

The binding of acetaminophen to plasma proteins is low (ranging from 10% to 25%), when given at therapeutic doses.

13.2 Ecological Information

13.2.1 EPA Ecotoxicity

Pesticide Ecotoxicity Data from EPA

13.2.2 Ecotoxicity Values

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

13.2.3 Ecotoxicity Excerpts

/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.
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 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.
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)

13.2.4 ICSC Environmental Data

The substance is toxic to aquatic organisms. It is strongly advised not to let the chemical enter into the environment.

13.2.5 Environmental Fate / Exposure Summary

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 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)

13.2.6 Artificial Pollution Sources

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)

13.2.7 Environmental Fate

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: https://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: https://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: https://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: https://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: https://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: https://webbook.nist.gov

13.2.8 Environmental Biodegradation

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.
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).
(1) Shelton DR, Tiedje JM; Appl Environ Microbiol 47: 449-69 (1984)

13.2.9 Environmental Abiotic Degradation

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: https://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: https://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)

13.2.10 Environmental Bioconcentration

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: https://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: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm/
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

13.2.11 Soil Adsorption / Mobility

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: https://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: https://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)

13.2.12 Volatilization from Water / Soil

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)

13.2.13 Environmental Water Concentrations

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.
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).
(1) Boyd GR et al; Sci Total Environ 311: 135-49 (2003)
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)

13.2.14 Effluent Concentrations

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)

13.2.15 Milk Concentrations

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

13.2.16 Probable Routes of Human Exposure

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: https://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: https://www.cdc.gov/noes/

14 Associated Disorders and Diseases

Disease
Colorectal cancer
References

PubMed: 7482520, 22148915, 19006102, 23940645, 24424155, 20156336, 19678709, 25105552, 21773981, 25037050, 27015276, 27107423, 27275383, 28587349

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

Disease
Eosinophilic esophagitis
References
Mordechai, Hien, and David S. Wishart

15 Literature

15.1 Consolidated References

15.2 NLM Curated PubMed Citations

15.3 Springer Nature References

15.4 Thieme References

15.5 Wiley References

15.6 Nature Journal References

15.7 Chemical Co-Occurrences in Literature

15.8 Chemical-Gene Co-Occurrences in Literature

15.9 Chemical-Disease Co-Occurrences in Literature

16 Patents

16.1 Depositor-Supplied Patent Identifiers

16.2 WIPO PATENTSCOPE

16.3 FDA Orange Book Patents

16.4 Chemical Co-Occurrences in Patents

16.5 Chemical-Disease Co-Occurrences in Patents

16.6 Chemical-Gene Co-Occurrences in Patents

17 Interactions and Pathways

17.1 Protein Bound 3D Structures

17.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

17.2 Chemical-Target Interactions

17.3 Drug-Drug Interactions

17.4 Drug-Food Interactions

  • Avoid alcohol. Alcohol may increase the risk of hepatotoxicity.
  • Take with or without food. The absorption is unaffected by food.

17.5 Pathways

18 Biological Test Results

18.1 BioAssay Results

19 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

20 Classification

20.1 MeSH Tree

20.2 NCI Thesaurus Tree

20.3 ChEBI Ontology

20.4 KEGG: Drug

20.5 KEGG: ATC

20.6 KEGG: Target-based Classification of Drugs

20.7 KEGG: JP15

20.8 KEGG: Risk Category of Japanese OTC Drugs

20.9 KEGG: OTC drugs

20.10 KEGG: Animal Drugs

20.11 KEGG: Drug Groups

20.12 WHO ATC Classification System

20.13 ChemIDplus

20.14 CAMEO Chemicals

20.15 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

20.16 ChEMBL Target Tree

20.17 UN GHS Classification

20.18 EPA CPDat Classification

20.19 NORMAN Suspect List Exchange Classification

20.20 CCSBase Classification

20.21 EPA DSSTox Classification

20.22 International Agency for Research on Cancer (IARC) Classification

20.23 EPA TSCA and CDR Classification

20.24 LOTUS Tree

20.25 FDA Drug Type and Pharmacologic Classification

20.26 EPA Substance Registry Services Tree

20.27 MolGenie Organic Chemistry Ontology

21 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
  2. CAMEO Chemicals
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    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
    CAMEO Chemical Reactivity Classification
    https://cameochemicals.noaa.gov/browse/react
  3. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  4. ChemIDplus
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  5. DrugBank
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  7. EPA Chemicals under the TSCA
    Acetamide, N-(4-hydroxyphenyl)-
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  9. European Chemicals Agency (ECHA)
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    acetaminophen, hydrocodone drug combination
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  23. Burnham Center for Chemical Genomics
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  29. Open Targets
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    CCSbase Classification
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    PARACETAMOL
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  33. Crystallography Open Database (COD)
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  35. DailyMed
  36. Drug Induced Liver Injury Rank (DILIrank) Dataset
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  37. European Medicines Agency (EMA)
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  38. Drugs and Lactation Database (LactMed)
  39. Drugs@FDA
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  63. WHO Anatomical Therapeutic Chemical (ATC) Classification
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  67. RCSB Protein Data Bank (RCSB PDB)
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  68. Springer Nature
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    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  71. Wikidata
  72. Wikipedia
  73. Wiley
  74. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  75. PubChem
  76. GHS Classification (UNECE)
  77. EPA Substance Registry Services
  78. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  79. PATENTSCOPE (WIPO)
  80. NCBI
CONTENTS