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Tromethamine

PubChem CID
6503
Structure
Tromethamine_small.png
Tromethamine_3D_Structure.png
Tromethamine__Crystal_Structure.png
Molecular Formula
Synonyms
  • Trometamol
  • TROMETHAMINE
  • 77-86-1
  • Tris(Hydroxymethyl)aminomethane
  • Tris
Molecular Weight
121.14 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-26
  • Modify:
    2025-01-18
Description
Tris is a primary amino compound that is tert-butylamine in which one hydrogen attached to each methyl group is replaced by a hydroxy group. A compound widely used as a biological buffer substance in the pH range 7--9; pKa = 8.3 at 20 ℃; pKa = 7.82 at 37 ℃. It has a role as a buffer. It is a triol and a primary amino compound. It is a conjugate base of a member of Htris.
An organic amine proton acceptor. It is used in the synthesis of surface-active agents and pharmaceuticals; as an emulsifying agent for cosmetic creams and lotions, mineral oil and paraffin wax emulsions, as a biological buffer, and used as an alkalizer. (From Merck, 11th ed; Martindale, The Extra Pharmacopoeia, 30th ed, p1424)
TROMETHAMINE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 1965 and is indicated for acidosis and has 7 investigational indications.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Tromethamine.png

1.2 3D Conformer

1.3 Crystal Structures

1 of 7
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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

2-amino-2-(hydroxymethyl)propane-1,3-diol
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C4H11NO3/c5-4(1-6,2-7)3-8/h6-8H,1-3,5H2
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

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

2.1.4 SMILES

C(C(CO)(CO)N)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C4H11NO3
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

77-86-1
1185-53-1
136760-04-8

2.3.2 Deprecated CAS

108195-86-4, 1158650-64-6, 119320-15-9, 25149-07-9, 68755-45-3, 83147-39-1, 857365-23-2
108195-86-4, 1158650-64-6, 119320-15-9, 68755-45-3, 83147-39-1, 857365-23-2

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 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 NSC Number

2.3.15 RXCUI

2.3.16 Wikidata

2.3.17 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Tri(hydroxymethyl)aminomethane
  • Tris Buffer
  • Tris(hydroxymethyl)aminomethane
  • Tris-Magnesium(II)-Potassium Chloride Buffer
  • Tris-Mg(II)-KCl Buffer
  • Trisamine
  • Trizma
  • Trometamol
  • Tromethamine

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
121.14 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
-2.9
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
121.07389321 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
121.07389321 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
86.7 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
8
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
54
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

Liquid; Other Solid
Solid; [Merck Index] White hygroscopic crystals; [Alfa Aesar MSDS]

3.2.2 Color / Form

Crystalline mass
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677
WHITE, CRYSTALLINE POWDER
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 773

3.2.3 Odor

SLIGHT, CHARACTERISTIC ODOR
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 773

3.2.4 Taste

FAINT, SWEET, SOAPY TASTE
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 773

3.2.5 Boiling Point

219-220 °C at 10 mm Hg
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677

3.2.6 Melting Point

171-172 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677

3.2.7 Solubility

79.1 mg/mL in ethylene glycol; 26 mg/mL in methanol; 14.6 mg/mL in anhyd ethanol; 22 mg/mL in 95% ethanol; 14 mg/mL in dimethyl formamide; 20 mg/mL in acetone; 0.5 mg/mL in ethyl acetate; 0.4 mg/mL in olive oil; 0.1 mg/mL in cyclohexane; 0.05 mg/mL in chloroform; less than 0.05 mg/mL in carbon tetrachloride
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677
In water, 5.50X10+5 mg/L at 25 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677

3.2.8 Vapor Pressure

0.000022 [mmHg]

3.2.9 Stability / Shelf Life

Stable in light and air
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 773

3.2.10 Decomposition

When heated to decomposition it emits toxic fumes of /nitrogen oxide/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3436

3.2.11 pH

pH of 0.1 molar aq soln = 10.4
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677

3.2.12 Ionization Efficiency

Ionization mode
Positive
logIE
2.41
pH
2.7
Instrument
Agilent XCT
Ion source
Electrospray ionization
Additive
formic acid (5.3nM)
Organic modifier
MeCN (80%)

3.2.13 Dissociation Constants

Basic pKa
8.08
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
pKa = 8.07
Perinn DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser: Suppl 1972. London, England: Buttersworth (1972)

3.2.14 Kovats Retention Index

Standard non-polar
1645

3.2.15 Other Experimental Properties

Weak, monoacidic base; aq soln do not absorb CO2 from air
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677
REACTS WITH PROTON DONORS
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 773

3.3 SpringerMaterials Properties

3.4 Chemical Classes

Other Uses -> Biological Buffers

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 -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.4.1.1 Human Drugs
Human drug -> Prescription
Human drug -> Prescription; Active ingredient (TROMETHAMINE)
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

Cosmetic ingredients (Tromethamine) -> CIR (Cosmetic Ingredient Review)
Buffering
S13 | EUCOSMETICS | Combined Inventory of Ingredients Employed in Cosmetic Products (2000) and Revised Inventory (2006) | DOI:10.5281/zenodo.2624118

3.4.3 Fragrances

Fragrance Ingredient (2-Amino-2-(hydroxymethyl)-1,3-propanediol) -> IFRA transparency List

4 Spectral Information

4.1 1D NMR Spectra

1 of 2
1D NMR Spectra
NMR: 6342 (Sadtler Research Laboratories Spectral Collection)
2 of 2
1D NMR Spectra

4.1.1 1H NMR Spectra

1 of 2
Instrument Name
BRUKER AC-300
Source of Sample
Tokyo Kasei Kogyo Company, Ltd., Tokyo, Japan
Copyright
Copyright © 1991-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
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2 of 2
Instrument Name
Varian A-60
Source of Sample
Aldrich Chemical Company, Inc., Milwaukee, Wisconsin
Copyright
Copyright © 2009-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.1.2 13C NMR Spectra

1 of 2
Source of Sample
Chem Service, Inc., West Chester, Pennsylvania
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Instrument Name
Jeol FX-200
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
Thumbnail
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4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 5
View All
NIST Number
229605
Library
Main library
Total Peaks
50
m/z Top Peak
90
m/z 2nd Highest
60
m/z 3rd Highest
42
Thumbnail
Thumbnail
2 of 5
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NIST Number
221178
Library
Replicate library
Total Peaks
36
m/z Top Peak
90
m/z 2nd Highest
60
m/z 3rd Highest
30
Thumbnail
Thumbnail

4.2.2 MS-MS

1 of 6
View All
Spectra ID
Instrument Type
LC-ESI-QQ
Ionization Mode
positive
Top 5 Peaks

122.2 100

104.1 16.34

104.9 5.18

50.0 1.13

87.3 0.58

Thumbnail
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Notes
instrument=API3000, Applied Biosystems
2 of 6
View All
Spectra ID
Instrument Type
LC-ESI-QQ
Ionization Mode
positive
Top 5 Peaks

104.1 100

122.2 54.35

56.1 51.88

57.0 35.81

105.2 19.74

Thumbnail
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Notes
instrument=API3000, Applied Biosystems

4.2.3 LC-MS

1 of 8
View All
Authors
Kakazu Y, Horai H, Institute for Advanced Biosciences, Keio Univ.
Instrument
API3000, Applied Biosystems
Instrument Type
LC-ESI-QQ
MS Level
MS2
Ionization Mode
POSITIVE
Collision Energy
10 V
Precursor m/z
122
Precursor Adduct
[M+H]+
Top 5 Peaks

122.2 999

104.1 163

104.9 52

50 11

87.3 6

Thumbnail
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License
CC BY-NC-SA
2 of 8
View All
Authors
Kakazu Y, Horai H, Institute for Advanced Biosciences, Keio Univ.
Instrument
API3000, Applied Biosystems
Instrument Type
LC-ESI-QQ
MS Level
MS2
Ionization Mode
POSITIVE
Collision Energy
20 V
Precursor m/z
122
Precursor Adduct
[M+H]+
Top 5 Peaks

104.1 999

122.2 543

56.1 518

57 358

105.2 197

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License
CC BY-NC-SA

4.2.4 Other MS

Other MS
MASS: 69526 (NIST/EPA/MSDC Mass SPectral database, 1990 version)

4.3 IR Spectra

IR Spectra
IR: 5998 (Coblentz Society Spectral Collection)

4.3.1 FTIR Spectra

1 of 2
Technique
KBr WAFER
Source of Sample
Polysciences, Inc., Warrington, Pennsylvania
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Technique
KBr WAFER
Source of Sample
Angus Chemical Company, Inc., Northbrook, Illinois
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.3.2 ATR-IR Spectra

1 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
T1503
Lot Number
SLBB6102V
Copyright
Copyright © 2014-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Source of Sample
Sigma-Aldrich
Catalog Number
T87602
Copyright
Copyright © 2018-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2018-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.3.3 Vapor Phase IR Spectra

1 of 2
Instrument Name
Bruker IFS 85
Technique
Gas-GC
Copyright
Copyright © 1989, 1990-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Source of Spectrum
Sigma-Aldrich Co. LLC.
Source of Sample
Sigma-Aldrich Co. LLC.
Catalog Number
154563
Copyright
Copyright © 2021-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2021 John Wiley & Sons, Inc. All Rights Reserved.
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4.4 Raman Spectra

1 of 2
Instrument Name
Bio-Rad FTS 175C with Raman accessory
Technique
FT-Raman
Source of Sample
Polysciences, Inc., Warrington, Pennsylvania
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Catalog Number
154563
Copyright
Copyright © 2017-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2017-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

For the prevention and correction of metabolic acidosis.

7.2 FDA Approved Drugs

7.3 FDA Orange Book

7.4 FDA National Drug Code Directory

7.5 Drug Labels

Drug and label
Active ingredient and drug

7.6 Clinical Trials

7.6.1 ClinicalTrials.gov

7.6.2 EU Clinical Trials Register

7.7 Therapeutic Uses

Buffers; Excipients
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
/Tromethamine is indicated/ for the prevention and correction of metabolic acidosis. /Included in US product label/
Novak, K.M. (ed.). Drug Facts and Comparisons 59th Edition 2005. Wolters Kluwer Health. St. Louis, Missouri 2005., p. 130
Metabolic Acidosis Associated with Cardiac Bypass Surgery. Tromethamine solution has been found to be primarily beneficial in correcting metabolic acidosis which may occur during or immediately following cardiac bypass surgical procedures. /Included in US product label/
Medical Economics Co; Physicians Desk Reference: Generics 2nd ed p.3033 (1996)
Correction of Acidity of ACD Blood in Cardiac Bypass Surgery. It is well known that ACD blood is acidic and becomes more acidic on storage. Tromethamine effectively corrects this acidity. Tromethamine solution may be added directly to the blood used to prime the pump-oxygenator. When ACD blood is brought to a normal pH range the patient is spared an initial acid load. Additional tromethamine may be indicated during cardiac bypass surgery should metabolic acidosis appear. /Included in US product label/
Medical Economics Co; Physicians Desk Reference: Generics 2nd ed p.3033 (1996)
For more Therapeutic Uses (Complete) data for TROMETHAMINE (6 total), please visit the HSDB record page.

7.8 Drug Warnings

Local reactions associated with administration of tromethamine may include local irritation and tissue inflammation or infection at the site of injection, a febrile response, chemical phlebitis, venospasm, hypervolemia, and iv thrombosis. The drug should be administered through a large needle or indwelling catheter to minimize venous irritation by the highly alkaline tromethamine solution. Extravasation may result in inflammation, necrosis, and sloughing of overlying skin. If perivascular infiltration occurs, tromethamine administration should be discontinued immediately. Infiltration of the affected area with 1% procaine hydrochloride, to which hyaluronidase has been added, will often reduce venospasm and also will dilute any tromethamine remaining in the tissues locally. Local infiltration of an alpha-adrenergic blocking agent, such as phentolamine mesylate, into the vasospastic area has been recommended. If necessary, nerve block of autonomic fibers to the affected area may be performed.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
Transient decreases in blood glucose concentration may occur during administration of tromethamine. When larger than recommended doses are used or when administration is too rapid, hypoglycemia may persist for several hours after the drug is discontinued.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
Tromethamine should be slowly administered and in amounts sufficient only to correct the existing acidosis, in order to avoid overdosage and alkalosis. Determinations of blood glucose concentrations should be frequently performed during and following therapy.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
Respiratory depression may occur in patients receiving large doses of tromethamine, as a result of increased blood pH and reduced carbon dioxide concentrations, and in those with chronic hypoventilation or those receiving other drugs that depress respiration. Dosage must be carefully adjusted so that blood pH does not increase above normal, and facilities for providing mechanical ventilation should be readily available during administration of tromethamine. Tromethamine may be used in conjunction with mechanical ventilatory support if respiratory acidosis is present concomitantly with metabolic acidosis.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
For more Drug Warnings (Complete) data for TROMETHAMINE (18 total), please visit the HSDB record page.

7.9 Reported Fatal Dose

3. 3= MODERATELY TOXIC: PROBABLY ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ & 1 PINT FOR 70 KG PERSON (150 LB).
Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976., p. II-74

8 Pharmacology and Biochemistry

8.1 MeSH Pharmacological Classification

Excipients
Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form. These include binders, matrix, base or diluent in pills, tablets, creams, salves, etc. (See all compounds classified as Excipients.)
Buffers
A chemical system that functions to control the levels of specific ions in solution. When the level of hydrogen ion in solution is controlled the system is called a pH buffer. (See all compounds classified as Buffers.)

8.2 ATC Code

B - Blood and blood forming organs

B05 - Blood substitutes and perfusion solutions

B05X - I.v. solution additives

B05XX - Other i.v. solution additives

B05XX02 - Trometamol

B - Blood and blood forming organs

B05 - Blood substitutes and perfusion solutions

B05B - I.v. solutions

B05BB - Solutions affecting the electrolyte balance

B05BB03 - Trometamol

8.3 Absorption, Distribution and Excretion

Tromethamine is substantially eliminated by the kidneys. ... Ionized tromethamine (chiefly as the bicarbonate salt) is rapidly and preferentially excreted in urine at a rate that depends on the infusion rate. The manufacturer states that urinary excretion continues over a period of 3 days; 75% or more appears in the urine after 8 hours. In some studies, 50-75% of an iv dose was recovered in urine within 24 hours, but another study reported recovery in healthy adults to be 64% and 77% after 2 and 3 days, respectively.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
It is not known whether tromethamine is distributed in human milk.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
Ionized tromethamine is excreted by kidney, so the effect is that of excretion of hydrogen ions. Elimination of drug from body is entirely by renal excretion. Excretion of tromethamine is accompanied by osmotic diuresis, since clinical doses of drug considerably add to osmolarity of glomerular filtrate.
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 773
In rats of different age (5 to 240 days old) the renal excretion of Trishydroxymethylaminomethane (THAM) was studied. In 5 and in 240 days old rats the renal excretion of THAM was slower than in rats of other age groups. Stimulation of diuresis by i.p. injection of mannitol, thiazide or by oral water load resulted in an increase in THAM excretion in 5 and in 240 days old rats. The renal excretion of THAM was also increased by repeated administration of THAM in all age groups, except in new born rats. Possible mechanisms of action are discussed.
Braunlich H; Arch Int Pharmacodyn Ther 216 (1): 144-59 (1975)
The distribution of 14C labelled THAM (tris-hydroxymethylaminomethane) was determined between intra- and extracellular space of nephrectomized Sprague-Dawley rats as a function of time at constant plasma pH of 7.4. The following results were obtained: An equilibrium in the distribution of THAM between ECS and ICS will not occur before 6-12 hours after administration. This indicates that THAM permeates very slowly into the intracellular compartment, which is in contrast to the general assumption that it quickly diffuses into the intracellular space to restore the intracellular acidosis. THAM disappears from the extracellular space in a multiexponential fashion, indicating that it equilibrates with the different body tissues at largely variable rates. The equilibrium which occurs between both body compartments 6-12 hours after THAM application does not agree with the values which are expected for transfer of only the nonionised substance. At plasma pH 7.4 and a "mean whole body pHi" of 6.88, THAM is distributed with a distribution ratio of 4 (ICS/ECS), a value quite different from the value of 11 which would be expected for exclusive nonionic diffusion. Thus THAM is also transferred across the cell membrane in ionized form. These results indicate that the influx of THAM into the intracellular space is too slow (when compared to the renal elimination kinetics) to influence intracellular pH significantly by direct buffer action. Moreover, only a fraction of THAM enters the intracellular space in the nonionized form, thus reducing (to an even greater extent) the direct effect of THAM on the intracellular acid-base equilibrium.
Rothe KF, Heisler N; Anasth Intensivther Notfallmed 19 (1): 24-6 (1984)

8.4 Metabolism / Metabolites

Tromethamine is not metabolized appreciably.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647

8.5 Mechanism of Action

Tromethamine is an alkalinizing agent which acts as a proton (hydrogen ion) acceptor. Tromethamine is a weak base; following IV injection, it attracts and combines with hydrogen ions and their associated acid anions and the resulting salts are excreted in urine. Tromethamine can combine with lactic, pyruvic, and other metabolic acids and with carbonic acid. ... At pH 7.4, approximately 70% of the tromethamine present in plasma is in the ionized (protonated) form; if pH is decreased from pH 7.4, the ionized fraction of the drug is increased. In contrast to the ionized fraction of tromethamine, which upon administration reacts only with acid in the extracellular fluids, the fraction of the dose which remains un-ionized at physiologic pH is thought to be capable of penetrating the cell membrane to combine with intracellular acid. Since administration of tromethamine reduces hydrogen ion concentration, there is a decrease in proton donor and an increase in proton acceptor concentrations in body buffers. In the bicarbonate:carbonic acid buffer, the concentration of dissolved carbon dioxide is decreased (at least until regulatory mechanisms compensate) and the concentration of bicarbonate is increased. The reduction of carbon dioxide tension removes a potent stimulus to breathing and may result in hypoventilation and hypoxia.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
Tromethamine ... acts as a weak, osmotic diuretic, increasing the flow of alkaline urine containing increased amounts of electrolytes.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
By removing protons from hydronium ions, ionization of carbonic acid is shifted so as to decrease pCO2 and to increase bicarbonate. Excess bicarbonate is then gradually excreted in kidney. /Tromethamine is an/ especially useful way to manage excessively high pCO2 in respiratory acidosis...
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 773

8.6 Human Metabolite Information

8.6.1 Tissue Locations

Placenta

9 Use and Manufacturing

9.1 Uses

Cosmetic Ingredient Review Link
CIR ingredient: Tromethamine
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
Used in chemical manufacturing (surface-active agents, vulcanization accelerators, and pharmaceuticals), as an emulsifying agent (cosmetics, mineral oil and paraffin wax emulsions, leather dressings, textile specialties, polishes, cleaning compounds, and soluble oils), and as an absorbent for acidic gases, biological buffer, acidimetric standard, and therapeutic alkalinizing agent; [Merck Index] Used in buffer systems for the freezer storage of sperm; [REPROTOX] Used in to regulate pH in the transport of live aquatic species, cell culture media, and anti-inflammatory drugs; [EPA ChAMP: Submission]
Merck Index - O'Neil MJ, Heckelman PE, Dobbelaar PH, Roman KJ (eds). The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, 15th Ed. Cambridge, UK: The Royal Society of Chemistry, 2013.
REPROTOX - Scialli AR, Lione A, Boyle Padgett GK. Reproductive Effects of Chemical, Physical, and Biological Agents. Baltimore: The Johns Hopkins University Press, 1995.
Industrial Processes with risk of exposure
In the synthesis of surface-active agents, vulcanization accelerators, pharmaceuticals. As emulsifying agent for cosmetic creams and lotions, mineral oil and paraffin wax emulsions, leather dressings, textile specialties, polishes, cleaning compounds, so-called soluble oils. Absorbent for acidic gases. Biological buffer.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1678
Therapeutic Category: Alkalinizing agent
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1678
MEDICATION
MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >500

Consumption (g per capita; approx.) in Germany (2009): 0.00611

Calculated removal (%): 92.1

9.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
Fragrance Ingredients
Cosmetics -> Buffering
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

9.1.2 Industry Uses

  • Laboratory chemicals
  • Other (specify)
  • Intermediates

9.1.3 Consumer Uses

  • Processing aids, not otherwise listed
  • Laboratory chemicals

9.1.4 Household Products

Household & Commercial/Institutional Products

Information on 2 consumer products that contain Tromethamine in the following categories is provided:

• Personal Care

9.2 Methods of Manufacturing

... Prepared by reduction of tris(hydroxymethyl)nitromethane.
Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V23 122 (2003)
May be prepared by reducation or catalytic hydrogenation of the corresponding nitro compd. ... Preparation by by electrolytic reduction: McMillan, US patent 2485982 (1949 to Comm Solvents Corp)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1677

9.3 Formulations / Preparations

Tromethamine formulations: Parenteral injection 36 mg/mL (18 g) Tham, Hospira.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
TROMETHAMINE, NF (THAM), IS AVAIL AS 0.3 MOLAR SOLN ADJUSTED TO PH 8.6 WITH ACETIC ACID. IT IS ALSO SUPPLIED AS POWDER (THAM-E) TO BE DISSOLVED IN 1 L OF STERILE WATER. EACH L CONTAINS 300 MMOLES (36 G) OF TROMETHAMINE, 30 MMOLES OF SODIUM CHLORIDE, & 5 MMOLES OF POTASSIUM CHLORIDE.
Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 775

9.4 U.S. Production

Aggregated Product Volume

2019: 1,000,000 lb - <20,000,000 lb

2018: 1,000,000 lb - <20,000,000 lb

2017: 1,000,000 lb - <20,000,000 lb

2016: 1,000,000 lb - <20,000,000 lb

Production volumes for non-confidential chemicals reported under the Inventory Update Rule.
Year
1986
Production Range (pounds)
>1 million - 10 million
Year
1990
Production Range (pounds)
>1 million - 10 million
Year
1994
Production Range (pounds)
>1 million - 10 million
Year
1998
Production Range (pounds)
>1 million - 10 million
Year
2002
Production Range (pounds)
>1 million - 10 million
US EPA; Non-confidential Production Volume Information Submitted by Companies for Chemicals Under the 1986-2002 Inventory Update Rule (IUR). 1,3-Propanediol, 2-amino-2-(hydroxymethyl)- (77-86-1). Available from, as of March 20, 2008: https://www.epa.gov/oppt/iur/tools/data/2002-vol.html
1,3-Propanediol, 2-amino-2-(hydroxymethyl)- is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438).
EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program. Available from the Database Query page at: https://www.epa.gov/hpv/pubs/general/opptsrch.htm on 1,3-Propanediol, 2-amino-2-(hydroxymethyl)- (77-86-1) as of March 20, 2008

9.5 General Manufacturing Information

Industry Processing Sectors
  • All Other Basic Organic Chemical Manufacturing
  • All Other Chemical Product and Preparation Manufacturing
  • Pharmaceutical and Medicine Manufacturing
EPA TSCA Commercial Activity Status
1,3-Propanediol, 2-amino-2-(hydroxymethyl)-: ACTIVE

10 Identification

10.1 Analytic Laboratory Methods

ELECTROPHORESIS.
Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982., p. 13/300-18.090
Analyte: tromethamine; 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., p.3429 (2007)
Analyte: tromethamine; matrix: chemical identification; procedure: reaction with salicylaldehyde and glacial acetic acid produces a yellow color
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.3429 (2007)
Analyte: tromethamine; matrix: chemical identification; procedure: reaction with ceric ammonium nitrate in nitric acid produces color change from light yellow to orange
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.3429 (2007)
For more Analytic Laboratory Methods (Complete) data for TROMETHAMINE (9 total), please visit the HSDB record page.

10.2 Clinical Laboratory Methods

GC METHOD FOR QUANTITATIVE DETERMINATION OF TRIS(HYDROXYMETHYL)AMINOMETHANE IN PLASMA.
HULSHOFF A, HB KOSTENBAUDER; GC METHOD FOR QUANTITATIVE DETERMINATION OF TRIS(HYDROXYMETHYL)AMINOMETHANE IN PLASMA; J CHROMATOGR 145(1) 155 (1978)
Analyte: tromethamine; matrix: blood (plasma, dried), amniotic fluid, cerebrospinal fluid, urine; procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm
Davey JF, Ersser RS; J Chromatogr 528: 9-23 (1990). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: tromethamine; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 237 nm; limit of detection: 282 ng/mL
Gumbhir K, Mason WD; J Chromatogr 583: 99-104 (1992). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: tromethamine; matrix: blood (plasma), urine; procedure: high-performance liquid chromatography with fluorescence detection at 460 nm (excitation) and 532 nm (emission); limit of quantitation: 5 ug/mL (urine); 1 ug/mL (plasma)
Morris MJ, Hsieh JYK; J Chromatogr 622: 87-92 (1993). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Note
Pictograms displayed are for 81.6% (958 of 1174) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 18.4% (216 of 1174) of reports.
Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements

H315 (81.5%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (81.6%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (71.9%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes

P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, 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 1174 reports by companies from 31 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria per 216 of 1174 reports by companies. For more detailed information, please visit ECHA C&L website.

There are 28 notifications provided by 958 of 1174 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.

11.1.2 Hazard Classes and Categories

Skin Irrit. 2 (81.5%)

Eye Irrit. 2 (81.6%)

STOT SE 3 (71.9%)

11.1.3 Hazards Summary

Not expected to be a skin sensitizer, based on similar compounds; Little if any human toxicity observed in many years of use in drugs and/or personal care products and cosmetics; [EPA ChAMP: Submission] A skin and strong eye irritant; [Alfa Aesar MSDS]

11.2 Accidental Release Measures

11.2.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.3 Handling and Storage

11.3.1 Storage Conditions

Tromethamine injection should be stored at 20-25 °C; freezing should be avoided. Unused portions of tromethamine solution should be discarded.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647

11.4 Regulatory Information

The Australian Inventory of Industrial Chemicals
Chemical: 1,3-Propanediol, 2-amino-2-(hydroxymethyl)-
REACH Registered Substance
New Zealand EPA Inventory of Chemical Status
2-amino-2-(hydroxymethyl)propane-1,3-diol: Does not have an individual approval but may be used under an appropriate group standard
New Zealand EPA Inventory of Chemical Status
.beta.-D-ribo-Hexopyranose, 1,6-anhydro-3-deoxy-2-O-(1-methylethyl)-4-O-(phenylmethyl)-: Does not have an individual approval but may be used under an appropriate group standard
New Zealand EPA Inventory of Chemical Status
Tromethamine: Does not have an individual approval but may be used under an appropriate group standard

11.4.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tromethamine, 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 15, 2005: https://www.fda.gov/cder/ob/

11.5 Other Safety Information

Chemical Assessment

IMAP assessments - 1,3-Propanediol, 2-amino-2-(hydroxymethyl)-: Environment tier I assessment

IMAP assessments - 1,3-Propanediol, 2-amino-2-(hydroxymethyl)-: Human health tier I assessment

12 Toxicity

12.1 Toxicological Information

12.1.1 Drug Induced Liver Injury

Compound
tromethamine
DILI Annotation
Ambiguous DILI-concern
Severity Grade
6
Label Section
Adverse reactions
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

12.1.2 Acute Effects

12.1.3 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ In studies of tromethamine administration in healthy individuals, the ventilatory rate remained constant, but a reduced tidal volume produced a decrease in minute ventilation and in carbon dioxide output; arterial oxygen saturation decreased by an average of about 5%.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2647
/SIGNS AND SYMPTOMS/ Too rapid administration and/or excessive amounts of tromethamine may cause alkalosis, hypoglycemia, overhydration or solute overload.
Medical Economics Co; Physicians Desk Reference: Generics 2nd ed p.3033 (1996)

12.1.4 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Even after neutralization, large oral doses in lab animals cause weakness, collapse, & coma (without convulsions). Injections of high doses in animals produce hypoglycemia, but concurrent administration of glucose does not prevent death.
Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976., p. II-74

12.1.5 Non-Human Toxicity Values

LD50 Rat iv 2300 mg/kg
Medical Economics Co; Physicians Desk Reference: Generics 2nd ed p.3033 (1996)
LD50 Rat oral 5900 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. 3436
LD50 Mouse iv 3500 mg/kg
Medical Economics Co; Physicians Desk Reference: Generics 2nd ed p.3033 (1996)

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Tromethamine's production and use as an emulsifying agent, in the synthesis of surface-active agents and vulcanization accelerators may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 2.2X10-5 mm Hg at 25 °C indicates that tromethamine is expected to exist in both the vapor and particulate phase in the ambient atmosphere. Vapor-phase tromethamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 11hours. Particulate-phase tromethamine is removed from the atmosphere by wet and dry deposition. Tromethamine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, an estimated Koc value of 1 indicates that tromethamine is expected to possess very high mobility in soil. The pKa of tromethamine is 8.07. Thus, this compound will partially exist in cation form in the environment and cations generally adsorb to organic carbon and clay more strongly than their neutral counterparts. As a result, tromethamine may have greater adsorption and less mobility than its estimated Koc value indicates. Volatilization from moist soil is not expected since cations do not volatilize and the estimated Henry's Law constant for the neutral species (free base) of tromethamine is 8.7X10-13 atm cu m/mol. Tromethamine is not expected to volatilize from dry soil surfaces based upon its estimated vapor pressure. Tromethamine yielded no oxygen uptake when incubated with pure cultures of different strains of bacteria, indicating biodegradation may be slow in the environment. If released to water, tromethamine is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. However, based on the pKa of 8.07, it should exist partially as a cation under environmental conditions (pH 5-9). As a result, tromethamine may have greater adsorption to suspended to solids and sediment than its estimated Koc value indicates. Volatilization from water surfaces will not be an important fate process since cations do not volatilize and given the estimated Henry's Law constant for the neutral species. 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. Occupational exposure to tromethamine may occur through inhalation and dermal contact with this compound at workplaces where tromethamine is produced or used. (SRC)

12.2.2 Artificial Pollution Sources

Tromethamine's production and use as an emulsifying agent, in the synthesis of surface-active agents and vulcanization accelerators(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ; Merck Index, 14th ed, Whitehouse Station, NJ Merck & Co. p 1677 (2006)

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that tromethamine is expected to have very high mobility in soil(SRC). However, tromethamine has a pKa of 8.07(3) and should exist partially as a cation under environmental conditions (pH 5-9)(SRC). As a result, tromethamine may have greater adsorption and less mobility than its estimated Koc value indicates since cations generally adsorb more strongly to soils containing organic carbon and clay than neutral species(4). Volatilization of tromethamine from moist soil surfaces is not expected to be an important fate process(SRC) since cations do not volatilize and the estimated Henry's Law constant for the neutral species is 8.7X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Tromethamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.2X10-5 mm Hg(SRC), determined from a fragment constant method(6).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Perinn DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser: Suppl 1972. London, England: Buttersworth (1972)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(6) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that tromethamine is not expected to adsorb to suspended solids and sediment(SRC). However, tromethamine has a pKa of 8.07(3) and should exist partially as a cation under environmental conditions (pH 5-9)(SRC). As a result, tromethamine may have greater adsorption to suspended solids and sediment than its estimated Koc value indicates(SRC). Volatilization from water is not expected(4) since cations do not volatilize and the estimated Henry's Law constant for the neutral species (free base) of tromethamine is 8.7X10-13 atm cu m/mol(SRC), calculated using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from an estimated log Kow of -1.56(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Perinn DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser: Suppl 1972. London, England: Buttersworth (1972)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990)
(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(6) Franke C et al; Chemosphere 29: 1501-14 (1994)
(7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tromethamine, which has a an estimated vapor pressure of 2.2X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase tromethamine 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 11 hours(SRC), calculated from its rate constant of 3.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase tromethamine is removed from the atmosphere by wet and dry deposition(SRC). Tromethamine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(4).
(1) Bidleman T.F.; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

12.2.4 Environmental Biodegradation

Tromethamine yielded no oxygen uptake when incubated with pure cultures of different strains of bacteria(1), indicating biodegradation may be slow in the environment.
(1) Kersters K, Deley J; Biochim Biophysica Acta 71: 311-331 (1963)

12.2.5 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of tromethamine with photochemically-produced hydroxyl radicals has been estimated as 3.4X10-11 cu cm/molecule-sec at 25 °C(SRC), using a structure estimation method(1). This corresponds to an atmospheric half-life of about 11 hours(SRC) at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Tromethamine is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). Tromethamine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to undergo direct photolysis by sunlight(2).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

12.2.6 Environmental Bioconcentration

An estimated BCF of 3 was calculated for tromethamine (SRC), using an estimated log Kow of -1.56(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) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of tromethamine can be estimated to be 1(SRC). According to a classification scheme(2), this estimated Koc value suggests that tromethamine is expected to have very high mobility in soil(SRC). The pKa of tromethamine is 8.07(3), indicating that this compound will partially exist as a cation in the environment. As a result, the mobility of tromethamine may be overestimated since cations generally adsorb more strongly to soils containing organic carbon and clay than neutral species(4).
(1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Perinn DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser: Suppl 1972. London, England: Buttersworth (1972)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

12.2.8 Volatilization from Water / Soil

Tromethamine is a weak base with pKa of 8.07(1). This estimated pKa indicates tromethamine will partially exist in the protonated form in the environment. Volatilization from moist soil and water is not expected since cations do not volatilize and the estimated Henry's Law constant for the neutral species (free base) of tromethamine is 8.7X10-13 atm cu m/mol(SRC), using a fragment constant estimation method(2). Tromethamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.2X10-5 mm Hg(SRC), determined from a fragment constant method(3).
(1) Perinn DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser: Suppl 1972. London, England: Buttersworth (1972)
(2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

12.2.9 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 40897 workers (30773 of these are female) are potentially exposed to tromethamine in the US(1). Occupational exposure to tromethamine may occur through inhalation and dermal contact with this compound at workplaces where tromethamine is produced or used(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 at https://www.cdc.gov/noes/ as of Dec 13, 2007.

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Nature Journal References

14.7 Chemical Co-Occurrences in Literature

14.8 Chemical-Gene Co-Occurrences in Literature

14.9 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 WHO ATC Classification System

18.6 ChemIDplus

18.7 ChEMBL Target Tree

18.8 UN GHS Classification

18.9 EPA CPDat Classification

18.10 NORMAN Suspect List Exchange Classification

18.11 EPA DSSTox Classification

18.12 International Agency for Research on Cancer (IARC) Classification

18.13 Consumer Product Information Database Classification

18.14 EPA TSCA and CDR Classification

18.15 EPA Substance Registry Services Tree

18.16 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    1,3-Propanediol, 2-amino-2-(hydroxymethyl)-
    https://services.industrialchemicals.gov.au/search-assessments/
    1,3-Propanediol, 2-amino-2-(hydroxymethyl)-
    https://services.industrialchemicals.gov.au/search-inventory/
  2. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  5. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  6. EPA Chemical Data Reporting (CDR)
    LICENSE
    The U.S. Government retains a nonexclusive, royalty-free license to publish or reproduce these documents, or allow others to do so, for U.S. Government purposes. These documents may be freely distributed and used for non-commercial, scientific and educational purposes.
    https://www.epa.gov/web-policies-and-procedures/epa-disclaimers#copyright
    1,3-Propanediol, 2-amino-2-(hydroxymethyl)-
    https://www.epa.gov/chemical-data-reporting
  7. EPA Chemicals under the TSCA
    1,3-Propanediol, 2-amino-2-(hydroxymethyl)-
    https://www.epa.gov/chemicals-under-tsca
    EPA TSCA Classification
    https://www.epa.gov/tsca-inventory
  8. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  9. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  10. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  11. Hazardous Substances Data Bank (HSDB)
  12. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  13. International Fragrance Association (IFRA)
    LICENSE
    (c) The International Fragrance Association, 2007-2021. All rights reserved.
    https://ifrafragrance.org/links/copyright
  14. New Zealand Environmental Protection Authority (EPA)
    LICENSE
    This work is licensed under the Creative Commons Attribution-ShareAlike 4.0 International licence.
    https://www.epa.govt.nz/about-this-site/general-copyright-statement/
  15. ChEBI
  16. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  17. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  18. IUPAC Digitized pKa Dataset
    propane, 2-amino-1,3-dihydroxy-2-hydroxymethyl-
    https://github.com/IUPAC/Dissociation-Constants
  19. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  20. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  21. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  22. Therapeutic Target Database (TTD)
  23. Consumer Product Information Database (CPID)
    LICENSE
    Copyright (c) 2024 DeLima Associates. All rights reserved. Unless otherwise indicated, all materials from CPID are copyrighted by DeLima Associates. No part of these materials, either text or image may be used for any purpose other than for personal use. Therefore, reproduction, modification, storage in a retrieval system or retransmission, in any form or by any means, electronic, mechanical or otherwise, for reasons other than personal use, is strictly prohibited without prior written permission.
    https://www.whatsinproducts.com/contents/view/1/6
    Consumer Products Category Classification
    https://www.whatsinproducts.com/
  24. Cosmetic Ingredient Review (CIR)
  25. EPA Chemical and Products Database (CPDat)
  26. Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
    LICENSE
    Copyright (c) 2022 Haz-Map(R). All rights reserved. Unless otherwise indicated, all materials from Haz-Map are copyrighted by Haz-Map(R). No part of these materials, either text or image may be used for any purpose other than for personal use. Therefore, reproduction, modification, storage in a retrieval system or retransmission, in any form or by any means, electronic, mechanical or otherwise, for reasons other than personal use, is strictly prohibited without prior written permission.
    https://haz-map.com/About
  27. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    TROMETAMOL
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  28. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  29. The Cambridge Structural Database
  30. DailyMed
  31. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  32. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  33. EU Clinical Trials Register
  34. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  35. NMRShiftDB
  36. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
    Tris(hydroxymethyl)aminomethane
    http://www.nist.gov/srd/nist1a.cfm
  37. Japan Chemical Substance Dictionary (Nikkaji)
  38. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
  39. Kruve Lab, Ionization & Mass Spectrometry, Stockholm University
    trizma base
  40. MassBank Europe
  41. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  42. Metabolomics Workbench
  43. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  44. Nature Chemical Biology
  45. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  46. SpectraBase
    2-AMINO-2-HYDROXYMETHYLPROPANE-1,3-DIOL
    https://spectrabase.com/spectrum/HE6RYROdPmk
    1,3-PROPANEDIOL, 2-AMINO-2-(HYDROXYMETHYL)-
    https://spectrabase.com/spectrum/JqauZfQCpEh
    TRIS(HYDROXYMETHYL)AMINOMETHANE, 99%
    https://spectrabase.com/spectrum/6NemRBIDHcf
    2-AMINO-2-(HYDROXYMETHYL)-1,3-PROPANEDIOL
    https://spectrabase.com/spectrum/DAVlacXwzxe
    2-amino-2-(hydroxymethyl)-1,3-propanediol
    https://spectrabase.com/spectrum/4ZaLbsVGQg2
    2-AMINO-2-(HYDROXYMETHYL)-1,3-PROPANEDIOL
    https://spectrabase.com/spectrum/CsEm9nId2Ns
    2-Amino-2-hydroxymethyl-1,3-propanediol
    https://spectrabase.com/spectrum/K9FkBgRhNdc
    TRIS(HYDROXYMETHYL)AMINOMETHANE, 99%
    https://spectrabase.com/spectrum/EqEJiTfJUjp
    Tris(hydroxymethyl)aminomethane
    https://spectrabase.com/spectrum/AZQu7hId8FZ
    2-Amino-2-hydroxymethyl-1,3-propanediol
    https://spectrabase.com/spectrum/FNDOF9WaGJs
    Tris(hydroxymethyl)aminomethane
    https://spectrabase.com/spectrum/3eX24Zaimg
    2-Amino-2-(hydroxymethyl)-1,3-propanediol
    https://spectrabase.com/spectrum/6Y1Owx0hzDq
    Tris(hydroxymethyl)aminomethane
    https://spectrabase.com/spectrum/Netbx9tDeS
  47. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  48. Springer Nature
  49. SpringerMaterials
  50. Thieme Chemistry
    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/
  51. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  52. Wikidata
  53. Wikipedia
  54. Wiley
  55. 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
  56. PubChem
  57. GHS Classification (UNECE)
  58. International Agency for Research on Cancer (IARC)
    LICENSE
    Materials made available by IARC/WHO enjoy copyright protection under the Berne Convention for the Protection of Literature and Artistic Works, under other international conventions, and under national laws on copyright and neighbouring rights. IARC exercises copyright over its Materials to make sure that they are used in accordance with the Agency's principles. All rights are reserved.
    https://publications.iarc.fr/Terms-Of-Use
    IARC Classification
    https://www.iarc.fr/
  59. EPA Substance Registry Services
  60. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  61. PATENTSCOPE (WIPO)
  62. NCBI
CONTENTS