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Dulcin

PubChem CID
9013
Structure
Dulcin_small.png
Dulcin_3D_Structure.png
Molecular Formula
Synonyms
  • Dulcin
  • 150-69-6
  • 1-(4-Ethoxyphenyl)urea
  • (4-ethoxyphenyl)urea
  • N-(4-Ethoxyphenyl)urea
Molecular Weight
180.20 g/mol
Computed by PubChem 2.2 (PubChem release 2025.09.15)
Dates
  • Create:
    2005-03-26
  • Modify:
    2025-11-15
Description
Dulcin appears as white crystals. (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.
Dulcin is a member of ureas.
structure

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Dulcin.png

1.2 3D Conformer

Interactive Chemical Structure Model
Conformer of 10

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(4-ethoxyphenyl)urea
Computed by Lexichem TK 2.9.3 (PubChem release 2025.09.15)

2.1.2 InChI

InChI=1S/C9H12N2O2/c1-2-13-8-5-3-7(4-6-8)11-9(10)12/h3-6H,2H2,1H3,(H3,10,11,12)
Computed by InChI 1.07.4 (PubChem release 2025.09.15)

2.1.3 InChIKey

GGLIEWRLXDLBBF-UHFFFAOYSA-N
Computed by InChI 1.07.4 (PubChem release 2025.09.15)

2.1.4 SMILES

CCOC1=CC=C(C=C1)NC(=O)N
Computed by OEChem 4.2.0 (PubChem release 2025.09.15)

2.2 Molecular Formula

C9H12N2O2
Computed by PubChem 2.2 (PubChem release 2025.09.15)

2.3 Other Identifiers

2.3.1 CAS

150-69-6
150696

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DSSTox Substance ID

2.3.7 HMDB ID

2.3.8 KEGG ID

2.3.9 Metabolomics Workbench ID

2.3.10 Nikkaji Number

2.3.11 NSC Number

2.3.12 Wikidata

2.3.13 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • dulcin
  • p-ethoxyphenylurea
  • phenetolcarbamide

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
180.20 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2025.09.15)
Property Name
XLogP3
Property Value
1
Reference
Computed by XLogP3 3.0 (PubChem release 2025.09.15)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.24 (PubChem release 2025.09.15)
Property Name
Hydrogen Bond Acceptor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.24 (PubChem release 2025.09.15)
Property Name
Rotatable Bond Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.24 (PubChem release 2025.09.15)
Property Name
Exact Mass
Property Value
180.089877630 Da
Reference
Computed by PubChem 2.2 (PubChem release 2025.09.15)
Property Name
Monoisotopic Mass
Property Value
180.089877630 Da
Reference
Computed by PubChem 2.2 (PubChem release 2025.09.15)
Property Name
Topological Polar Surface Area
Property Value
64.4 Ų
Reference
Computed by Cactvs 3.4.8.24 (PubChem release 2025.09.15)
Property Name
Heavy Atom Count
Property Value
13
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
165
Reference
Computed by Cactvs 3.4.8.24 (PubChem release 2025.09.15)
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 2025.09.15)

3.2 Experimental Properties

3.2.1 Physical Description

Dulcin appears as white crystals. (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.
Solid

3.2.2 Color / Form

White needle-like crystals or powder
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 484
Lustrous needles
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 587
Leafs (from dilute alcohol), plates (from water)
Haynes, W.M. (ed.) CRC Handbook of Chemistry and Physics. 91st ed. Boca Raton, FL: CRC Press Inc., 2010-2011, p. 3-236

3.2.3 Taste

Very sweet taste, about 250 times as sweet as sugar cane
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 587

3.2.4 Boiling Point

Decomposes (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.
Decomposes
Haynes, W.M. (ed.) CRC Handbook of Chemistry and Physics. 91st ed. Boca Raton, FL: CRC Press Inc., 2010-2011, p. 3-236

3.2.5 Melting Point

343 to 345 °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.
173.5 °C
Haynes, W.M. (ed.) CRC Handbook of Chemistry and Physics. 91st ed. Boca Raton, FL: CRC Press Inc., 2010-2011, p. 3-236
173 - 174 °C

3.2.6 Solubility

Slightly soluble (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.
In water, 1.21 g/L at 21 °C
Yalkowsky, S.H., He, Yan, Jain, P. Handbook of Aqueous Solubility Data Second Edition. CRC Press, Boca Raton, FL 2010, p. 601
Soluble in 800 parts cold water, 50 parts boiling water, 25 parts alcohol
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 587
1.21 mg/mL at 21 °C

3.2.7 Decomposition

When heated to decomposition it emits toxic fumes of /oxides of nitrogen/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1622

3.2.8 Collision Cross Section

149.7 Ų [M+Na]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID9020580]

144.5 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID9020580]

144.1 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID9020580]

3.2.9 Other Experimental Properties

Partially decomposes on heating with water; hydrolyzes in N acetic acid
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. V12: 97 (1976)

3.3 Chemical Classes

3.3.1 Food Additives

NON-NUTRITIVE SWEETENER -> FDA Substance added to food

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 1H NMR Spectra

Instrument Name
BRUKER AC-300
Source of Sample
Aldrich Chemical Company, Inc., Milwaukee, Wisconsin
Copyright
Copyright © 1991-2025 John Wiley & Sons, Inc. All Rights Reserved.
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4.1.2 13C NMR Spectra

Source of Sample
Eastman Organic Chemicals, Rochester, New York
Copyright
Copyright © 1980, 1981-2025 John Wiley & Sons, Inc. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 3 items
View All
NIST Number
241952
Library
Main library
Total Peaks
88
m/z Top Peak
108
m/z 2nd Highest
180
m/z 3rd Highest
109
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2 of 3 items
View All
NIST Number
256475
Library
Replicate library
Total Peaks
63
m/z Top Peak
108
m/z 2nd Highest
109
m/z 3rd Highest
180
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4.2.2 MS-MS

1 of 6 items
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

108.0444 100

65.0386 61.26

110.0601 32.03

81.0335 27.33

111.0441 23.82

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2 of 6 items
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

181.0971 100

138.0913 26.93

136.0758 19.72

110.06 4.70

164.0705 4.60

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4.2.3 LC-MS

1 of 9 items
View All
Authors
Elapavalore, A.; Kondić, T.; Singh, R.; Schymanski, E.
Instrument
Q Exactive Orbitrap (Thermo Scientific)
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
15
Fragmentation Mode
HCD
Column Name
Acquity BEH C18 1.7um, 2.1x150mm (Waters)
Retention Time
13.186 min
Precursor m/z
181.0972
Precursor Adduct
[M+H]+
Top 5 Peaks

181.0971 999

138.0913 269

136.0758 197

110.06 47

164.0705 46

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License
CC BY
Reference
Elapavalore, A.; Kondić, T.; et al., Adding Open Spectral Data to MassBank and PubChem Using Open Source Tools to Support Non-Targeted Exposomics of Mixtures (submitted).
2 of 9 items
View All
Authors
Elapavalore, A.; Kondić, T.; Singh, R.; Schymanski, E.
Instrument
Q Exactive Orbitrap (Thermo Scientific)
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
30
Fragmentation Mode
HCD
Column Name
Acquity BEH C18 1.7um, 2.1x150mm (Waters)
Retention Time
13.186 min
Precursor m/z
181.0972
Precursor Adduct
[M+H]+
Top 5 Peaks

181.0972 999

138.0914 356

136.0759 296

110.0601 77

164.0706 56

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License
CC BY
Reference
Elapavalore, A.; Kondić, T.; et al., Adding Open Spectral Data to MassBank and PubChem Using Open Source Tools to Support Non-Targeted Exposomics of Mixtures (submitted).

4.2.4 Other MS

1 of 4 items
View All
Other MS
MASS: 7462 (NIST/EPA/MSDC Mass Spectral Database, 1990 Version)
2 of 4 items
View All
Authors
EPA CCTE and Agilent Technologies
Instrument Type
ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20
Precursor m/z
181.0971541
Precursor Adduct
[M+H]+
Top 5 Peaks

108.04439 999

110.06004 745

136.07569 379

138.09134 302

93.033491 166

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License
CC BY

4.3 UV Spectra

Adsorption max at 290 nm and 242 nm in ethanol (epsilon = 110 and 1001)
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. V12: 97 (1976)
UV: 5-184 (Phillip et al, Organic Electronic Spectral Data, John Wiley & Sons, New York)
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. V5: 5198

4.4 IR Spectra

4.4.1 FTIR Spectra

Technique
KBr WAFER
Source of Sample
EASTMAN ORGANIC CHEMICALS, ROCHESTER, NEW YORK
Catalog Number
589
Copyright
Copyright © 1980, 1981-2025 John Wiley & Sons, Inc. All Rights Reserved.
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4.5 Raman Spectra

Copyright
Copyright © 2024-2025 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

61 vendors
PubChem SID: 482318725
Purchasable Chemical: DRE-C13097500
PubChem SID: 485273580
Purchasable Chemical: TRC-D720450
PubChem SID: 496024078
Purchasable Chemical: TRC-D720450-10G
PubChem SID: 439455599
Purchasable Chemical: bt-311904
PubChem SID: 254767213
Purchasable Chemical: 150-69-6
PubChem SID: 488427305
Purchasable Chemical: B0001-167332
PubChem SID: 508745787
Purchasable Chemical: E89827
PubChem SID: 131299822
Purchasable Chemical: A809064
PubChem SID: 473092046
Purchasable Chemical: sc-257566
PubChem SID: 504751780
Purchasable Chemical: E156210
PubChem SID: 476223089
Purchasable Chemical: DY791692
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Purchasable Chemical: Amb1195896
PubChem SID: 491123319
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PubChem SID: 164803532
Purchasable Chemical: FT-0618389
PubChem SID: 484263078
Purchasable Chemical: 4653-1-X1
PubChem SID: 513858232
Purchasable Chemical: 85818
PubChem SID: 468722797
Purchasable Chemical: JH152847
PubChem SID: 439361522
Purchasable Chemical: S591437
CATO Research Chemicals Inc. (Chemical Vendors, Research and Development)
PubChem SID: 513785730
Purchasable Chemical: CCHM701123
PubChem SID: 434429441
Purchasable Chemical: CSSB00000181708
PubChem SID: 187565363
Purchasable Chemical: PS-4228
PubChem SID: 374156528
Purchasable Chemical: AA001M5E
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PubChem SID: 384284781
Purchasable Chemical: AG129748
PubChem SID: 517727616
Purchasable Chemical: SY050777
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Purchasable Chemical: D746194
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Purchasable Chemical: SBB089673
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Purchasable Chemical: ST45136785
PubChem SID: 463614513
Purchasable Chemical: CS-0206739
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PubChem SID: 483722052
Purchasable Chemical: ST001NOY
PubChem SID: 481125190
Purchasable Chemical: BD7918131
PubChem SID: 169943220
Purchasable Chemical: MCULE-3095219240
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PubChem SID: 507567783
Purchasable Chemical: EC001ODY
PubChem SID: 377399070
Purchasable Chemical: A262662
PubChem SID: 355163618
Purchasable Chemical: R058539
PubChem SID: 316463704
Purchasable Chemical: AB238678
PubChem SID: 473144224
Purchasable Chemical: PI-50301
PubChem SID: 518384688
Purchasable Chemical: IBS-L0232666
PubChem SID: 472479299
Purchasable Chemical: R005397
PubChem SID: 406677737
Purchasable Chemical: 100935
PubChem SID: 506190220
Purchasable Chemical: CAS-150-69-6
PubChem SID: 329794746
Purchasable Chemical: CDS021482_ALDRICH
PubChem SID: 374128155
Purchasable Chemical: SS-7038
PubChem SID: 335669884
Purchasable Chemical: Z56754688
PubChem SID: 508419876
Purchasable Chemical: ACRIAP687
PubChem SID: 478214587
Purchasable Chemical: TH-C041256
PubChem SID: 104661951
Purchasable Chemical: AKOS000113528
PubChem SID: 354333825
Purchasable Chemical: E1171
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PubChem SID: 375295222
Purchasable Chemical: BD127026
PubChem SID: 490686333
Purchasable Chemical: 859151
PubChem SID: 497657037
Purchasable Chemical: TX001NDU
PubChem SID: 470383425
Purchasable Chemical: CQ_150-69-6
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Purchasable Chemical: B141269
PubChem SID: 406560609
Purchasable Chemical: AR001MX6
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PubChem SID: 508601725
Purchasable Chemical: F6660-3429
PubChem SID: 504088349
Purchasable Chemical: HY-W150251
PubChem SID: 486233296
Purchasable Chemical: MC791692
PubChem SID: 440079146
Purchasable Chemical: AD09824
PubChem SID: 458835908
Purchasable Chemical: T71814
PubChem SID: 443821989
Purchasable Chemical: AA75262

7 Food Additives and Ingredients

7.1 Food Additive Classes

JECFA Functional Classes
Food Additives -> SWEETENER;

7.2 FDA Substances Added to Food

Used for (Technical Effect)
NON-NUTRITIVE SWEETENER
Document Number (21 eCFR)

7.3 Evaluations of the Joint FAO / WHO Expert Committee on Food Additives - JECFA

Chemical Name
SUCROL
Evaluation Year
1967
ADI
NOT TO BE USED

8 Pharmacology and Biochemistry

8.1 Absorption, Distribution and Excretion

After its oral administration to rats, dulcin is absorbed rapidly and is distributed throughout the body, with highest concentrations in the liver, kidneys, brain and lungs; tissue levels diminished to one-tenth within 24 hours after dosing.
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. V12 101 (1976)

8.2 Metabolism / Metabolites

... /Dulcin (DL)/ is excreted as a urinary ureido-N-glucuronide after oral administration to rabbits. ... Seven /UDP-glucuronosyltransferase (UGT)/ isoforms (UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT2B13, UGT2B14, and UGT2B16) have been identified from rabbit liver, but these UGTs have not been investigated using DL as a substrate. In this work, the identities of UGT isoforms catalyzing the formation of DL glucuronide were investigated using rabbit liver microsomes (RabLM) and cloned/expressed as rabbit UGT isoforms. DL-N-glucuronide (DNG) production was determined quantitatively in RabLM and homogenates of COS-7 cells expressing each UGT isoform by using electrospray liquid chromatography-tandem mass spectrometry. Analysis of DNG formation using RabLM, by Eadie-Hofstee plot, gave a Vmax of 0.911 nM/min/mg protein and the Km of 1.66 mM. DNG formation was catalyzed only by cloned expressed rabbit UGT1A7 and UGT2B16 (Vmax of 3.98 and 1.16 pmol/min/mg protein and a Km of 1.23 and 1.69 mM, respectively). Substrate inhibition of UGT1A7 by octylgallate confirmed the significant contribution of UGT1A7 to the formation of DNG. Octylgallate was further shown to competitively inhibit DNG production by RabLM (Ki = 0.149 mM). These results demonstrate that UGT1A7 is the major isoform catalyzing the N-glucuronidation of DL in RabLM.
Uesawa Y et al; Drug Metab Dispos 32 (12): 1476-8 (2004)
... Dulcin (DL) possesses an ureido group that is metabolized by direct glucuronidation in rabbit liver microsomes. ...The glucuronidation of DL was studied using human liver microsomes (HLM) and expressed human UDP-glucuronosyltransferase (UGT) enzymes. The average K (m) and V (max) values from nine HLM samples were 2.10 mM and 0.156 nmol/mg/min, respectively. Of the six human UGT isoforms screened for their ability to glucuronidate DL, only UGT1A1 and UGT1A9 showed activity. The apparent K (m) values using UGT1A1 and UGT1A9 were 5.06 and 6.99 mM, and the apparent V (max) values were 0.0461 and 0.106 nmol/min/mg, respectively. Phenolphthalein, a substrate for UGT1A9, inhibited DL glucuronidation in HLM competitively (K (i) = 0.356 mM), but bilirubin, a substrate for UGT1A1, did not. These results suggest that UGT1A9 is a key enzyme catalyzing the glucuronidation of DL.
Uesawa Y et al; Arch Toxicol 81 (3): 163-8 (2007)
/It was/ found that 3% of a dose of dulcin was excreted unchanged in the urine of treated rabbits, 27% was excreted as dulcin N-glucuronide, a further 40% was excreted collectively as para-hydroxyphenylurea and its O-sulphate and O-glucuronide, and there were small amounts of urinary para-aminophenol.
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. V12 101 (1976)
Dulcin has known human metabolites that include (2S,3S,4S,5R)-6-[(4-ethoxyphenyl)carbamoylamino]-3,4,5-trihydroxyoxane-2-carboxylic acid.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

8.3 Mechanism of Action

Behaviors and taste-nerve responses to bitter stimuli are linked to compounds that bind T2 receptors expressed in one subset of taste-bud receptor cells (TRCs); and behavioral and neural responses to sweet stimuli are linked to chemical compounds that bind a T1 receptor expressed in a different TRC subset. Neural and behavioral responses to bitter-sweet mixtures, however, complicate the ostensible bitter and sweet labeled lines. In the golden hamster, Mesocricetus auratus, quinine hydrochloride, the bitter prototype, suppresses chorda tympani (CT) nerve responses to the sweet prototype: sucrose. This bitter-sweet inhibition was tested with concentration series of sucrose and dulcin, a hydrophobic synthetic sweetener that hamsters behaviorally cross-generalize with sucrose. Dulcin, sucrose and other sweeteners activate one subset of CT fibers: S neurons; whereas, quinine activates a separate subset of CT fibers: E neurons. Whole-nerve and S-neuron CT responses to a sweetener concentration series, mixed with 0, 1, 3 and 10 mM quinine, were measured for 0-2.5 s transient and/or 2.6-10 s steady-state response periods. Ten-sec total single-fiber records, aligned at response onset, were averaged for 100 ms bins to identify response oscillations. Quinine inhibition of dulcin and sucrose responses was identical. Each log molar increment in quinine resulted in equivalent declines in response to either sweetener. Furthermore, sucrose response decrements paralleled response increments in quinine-sensitive CT neurons to the same quinine increases. A 1.43 Hz bursting rhythm to the sweeteners was unchanged by quinine inhibition or decreases in sweetener concentration. Taste-bud processing, possibly between-cell inhibition and within-cell negative feedback, must modify signals initiated by T1 receptors before they are transmitted to the brain.
Frank ME et al; Brain Res Bull 66 (1): 70-84 (2005
Variations in amplitude of responses of the chorda tympani to repeated application of various novel tastants were measured in familiarized and control groups of adult hamsters. Three groups of 10 hamsters were pre-exposed to 5 mM dulcin, 50 mM potassium L-glutamate (KGlu) or 1 mM 5'guanosine monophosphate (5'GMP). In the fourth group, the tongue was rinsed with 5'GMP for 20 min just prior to recording from the chorda tympani. The tastants were novel to the fifth group (naive control). A series of 17 stimuli was repeated six times and responses were quantified relative to the initial response of each of the 50 hamsters. The responses of the chorda tympani increased with repetition in the control group. In contrast, no increase in amplitude of response to the pre-exposed tastants or to stimuli with qualitatively related tastes was observed in the group familiarized with either KGlu or 5'GMP. These results indicate that the response of the chorda tympani depends on previous exposure to a tastant. The sensitivity of taste cells appears to be modulated, possibly by stimulus-induced supplementary receptors.
Berteretche MV et al; Appetite 45 (3): 324-33 (2005)
... /Investigators/ studied the role of alpha-gustducin in sweet taste. The behavioral and electrophysiological responses of alpha-gustducin knockout (KO) and wild-type (WT) mice to 11 different sweeteners, representing carbohydrates, artificial sweeteners, and sweet amino acids /was compared/. In behavioral experiments, over 48-h preference ratios were measured in two-bottle preference tests. In electrophysiological experiments, integrated responses of chorda tympani (CT) and glossopharyngeal (NG) nerves were recorded. /It was/ found that preference ratios of the KO mice were significantly lower than those of WT for acesulfame-K, dulcin, fructose, NC00174, D-phenylalanine, L-proline, D-tryptophan, saccharin, SC45647, sucrose, but not neotame. The nerve responses to all sweeteners, except neotame, were smaller in the KO mice than in the WT mice. The differences between the responses in WT and KO mice were more pronounced in the CT than in the NG. These data indicate that alpha-gustducin participates in the transduction of the sweet taste in general.
Danilova V et al; Chem Senses 31 (6): 573-80 (2006)

8.4 Human Metabolite Information

8.4.1 Cellular Locations

  • Cytoplasm
  • Extracellular

8.5 Transformations

1 item
Predecessor
Predecessor
Predecessor Name
Successor
Successor
Successor Name
Transformation
O-glucuronidation / Human Phase II
Enzyme
Evidence DOI

9 Use and Manufacturing

9.1 Uses

Artificial sweetening agent, prohibited by FDA for use in foods.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 484
Non-nutritive sweetener
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 587

9.1.1 Use Classification

Food Additives -> SWEETENER; -> JECFA Functional Classes

9.2 Methods of Manufacturing

From p-aminophenol
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 484
... Produced from the addition of potassium cyanate to p-phenetidine hydrochloride in aqueous solution at room temperature or from mixing urea and p-phenetidine hydrochloride to a mixture of hydrochloric acid and glacial acetic acid.
Nitschke C, Scherr G; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2012). NY, NY: John Wiley & Sons; Urea Derivatives. Online Posting Date: October 15, 2010
Made by treating p-phenetidine with phosgene and then with ammonia.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 587

9.3 General Manufacturing Information

Dulcin achieved some practical importance as a sweetener, despite safety concerns. It was blended with saccharin or sodium saccharin in order to mask the aftertaste of saccharin. As some dulcin metabolites were considered potentially hazardous, it is now banned in most countries.
von Rymon Lipinski G-W; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2012). NY, NY: John Wiley & Sons; Sweeteners. Online Posting Date: June 15, 2000
Compared with dilute sucrose solutions, it is approximately 250 times sweeter. Sweetness characteristics are good.
von Rymon Lipinski G-W; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2012). NY, NY: John Wiley & Sons; Sweeteners. Online Posting Date: June 15, 2000

10 Identification

10.1 Analytic Laboratory Methods

Dulcin has been determined by thin-layer chromatography in carbonated drinks and fruit juices, with limits of detection of 5 and 7 mg/kg, respectively; in a variety of soft drinks, with a limit of detection of 0.03%: and in some Japanese foods, with a limit of detection of 1-8 ug/mL. A detailed method for its determination in food products, with a detection limit ranging from 0.01-2 ug depending on the chromogenic spray reagent employed, includes a preliminary column chromatography clean-up. A comparison has been made of the sensitivity of different spray reagents on different thin-layer chromatography substrates, with detection limits for dulcin ranging from 0.1-1.0 ug. Paper chromatography has been used for its detection in foods, with a limit of 12.5 ug and in wine.
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. V12 99 (1976)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (50%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (50%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

ECHA C&L Notifications Summary

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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. For more detailed information, please visit ECHA C&L website.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (50%)

Skin Irrit. 2 (50%)

Eye Irrit. 2 (50%)

11.1.3 Health Hazards

SYMPTOMS: Ingestion of 20-40 g in adults produced dizziness, nausea, methemoglobinemia with cyanosis and hypotension.

ACUTE/CHRONIC HAZARDS: When heated produces hazardous decomposition products. (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.

11.2 First Aid Measures

11.2.1 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.

11.3 Accidental Release Measures

11.3.1 Disposal Methods

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal and plant life; and conformance with environmental and public health regulations.

11.4 Handling and Storage

11.4.1 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 ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 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 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 store this material in a refrigerator. (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.

11.5 Exposure Control and Personal Protection

11.5.1 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.

11.6 Stability and Reactivity

11.6.1 Air and Water Reactions

Partially decomposes on heating in water; hydrolyzes in 0.1 N acetic acid. Slightly water soluble (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.

11.6.2 Reactive Group

Amides and Imides

Amines, Aromatic

11.6.3 Reactivity Alerts

Water-Reactive

11.6.4 Reactivity Profile

DULCIN is an example of an amide. Amides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

11.7 Regulatory Information

11.7.1 FDA Requirements

Substances generally prohibited from direct addition or use as human food. ... Food containing any added or detectable level of dulcin is deemed to be adulterated in violation of the act, based upon an order published in the Federal Register of January 19, 1950 (15 FR 321).
21 CFR 189.145 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of June 19, 2012: https://www.ecfr.gov

12 Toxicity

12.1 Toxicological Information

12.1.1 Carcinogen Classification

IARC Carcinogenic Agent
Dulcin
IARC Carcinogenic Classes
Group 3: Not classifiable as to its carcinogenicity to humans
IARC Monographs

Volume 12: (1976) Some Carbamates, Thiocarbamates and Carbazides

Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)

12.1.2 Acute Effects

7 items
Compound CID
Organism
women
Test Type
TDLo
Route
oral
Dose
600 mg/kg
Effect
BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); BEHAVIORAL: HALLUCINATIONS, DISTORTED PERCEPTIONS; BEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY)
Reference
Medizinische Klinik., 43(105), 1948
Compound CID
Organism
child
Test Type
LDLo
Route
oral
Dose
400 mg/kg
Effect
BEHAVIORAL: HALLUCINATIONS, DISTORTED PERCEPTIONS; BEHAVIORAL: MUSCLE WEAKNESS; GASTROINTESTINAL: NAUSEA OR VOMITING
Reference
Medizinische Klinik., 43(105), 1948
Compound CID
Organism
rat
Test Type
LD50
Route
oral
Dose
3200 mg/kg
Effect
Reference
Arzneimittel-Forschung. Drug Research., 8(150), 1958 [PMID:13535335]
Compound CID
Organism
mouse
Test Type
LD50
Route
oral
Dose
700 mg/kg
Effect
Reference
FAO Nutrition Meetings Report Series., 44A(100), 1967
Compound CID
Organism
mouse
Test Type
LDLo
Route
intraperitoneal
Dose
135 mg/kg
Effect
BEHAVIORAL: GENERAL ANESTHETIC; BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)
Reference
Journal of Pharmacology and Experimental Therapeutics., 54(188), 1935
Page of 2

12.1.3 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

12.1.4 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ Thorough studies on human volunteers, including several diabetics, showed that the ingestion of 0.1-0.6 g dulcin/day for one year produced no adverse effects.
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. V12 101 (1976)
/SIGNS AND SYMPTOMS/ In adults, doses of 20-40 g dulcin produces dizziness, nausea, methemoglobin with cyanosis, hypotension and, in one case, coronary disturbance.
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. V12 101 (1976)
/CASE REPORTS/ Two deaths in children have been associated with the ingestion of 8-10 g dulcin.
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. V12 101 (1976)
/OTHER TOXICITY INFORMATION/ ...The glucuronidation of /dulcin (DL)/ was studied using human liver microsomes (HLM) and expressed human UDP-glucuronosyltransferase (UGT) enzymes. ... Phenolphthalein, a substrate for UGT1A9, inhibited DL glucuronidation in HLM competitively (K (i) = 0.356 mM), but bilirubin, a substrate for UGT1A1, did not. ...
Uesawa Y et al; Arch Toxicol 81 (3): 163-8 (2007)
/OTHER TOXICITY INFORMATION/ Psychophysical cross-adaptation experiments were performed with two carbohydrates, sucrose (SUC) and fructose (FRU), and two sweeteners, acesulfame-K (MOD) and dulcin (DUL). Seven subjects were asked to match concentrations that elicited the same intensity as a sucrose reference (30 g/L). Cross-adaptation levels were calculated as the ratio of isointense concentrations measured for a given stimulus before and under adaptation. ... Significant and reciprocal cross-enhancement is observed between DUL and MOD (approximately -20%, P < 0.03), and also between SUC and DUL (approximately -15%, P < 0.08). In parallel, molecular modeling of the four tastants was performed in order to look for the 12 common binding motifs that were isolated on 14 other tastants in a previous study. ...DUL and MOD only display four and five distinct motifs respectively and do not have any motif in common. Experimental cross-adaptation levels seem to correlate well with the number of motifs that molecules have in common. ...DUL and MOD do not share any motif and do not cross-adapt. ...
Froloff N et al; Chem Senses 23 (2): 197-206 (1998)

12.1.5 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of 20 male and 30 female rats was given oral incubations of 0.2 g/kg bw/day dulcin in Tween-methyl cellulose solution for 400 days (total dose, 17 g), at which time 60% of the animals were still alive. Half of these animals received no dulcin from then on and were observed until death; the remaining animals continued to receive the dulcin treatment, and total doses of up to 33 g/animal were given. No malignant tumors were reported. Of 30 controls given the Tween-methyl cellulose vehicle alone, one developed a fibroadenoma. During the experiment an unstated number of treated males and 20 treated females were mated; the 39 male offspring were treated at 8 weeks of age with 0.2 g/kg bw/day for 660 days (total dose, 29 g), at which time the 5 survivors were killed. No malignant tumors were reported.
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. V12 100 (1976)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of 80 white rats (sex unspecified) received different doses of dulcin for lifespan. Fifteen rats receiving 0.2 g/kg bw/day survived 12 months, and the last rat survived 22 months; no carcinogenic effect was seen.
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. V12 100 (1976)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of 30 14-week old rats (mainly male, strain not specified) was fed 20 g of a diet containing 1% commercial dulcin (m.p. 169-170 °C) daily for up to 24 months. Thirty rats fed the basal diet alone served as controls. All of 30 rats which received a diet containing 0.1% butter yellow and served as positive controls died with liver tumors within 21-24 months. After one year, 26 dulcin-treated rats and 26 controls were alive; by the end of the experiment, 9 treated and 13 control rats were still alive. Papillomas of the pelvic epithelium and of the bladder occurred in about 75% of 23 treated animals and in none of 19 controls. Stones were present in the renal pelvis and bladder of about 66% of the 23 treated animals. All stones were associated with papillomas, but the papillomas did not always occur in the area of the urinary tract where the stone was located.
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. V12 100 (1976)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 10-25 male rats (strain not specified) were fed diets containing 0, 0.001, 0.01, 0.1, 0.5 or 1% dulcin for 2 years. After 18 months, 7/10, 7/10, 7/10, 8/20, 7/20 and 4/25 rats in the respective groups were still alive; no liver tumors were observed.
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. V12 100 (1976)
For more Non-Human Toxicity Excerpts (Complete) data for Dulcin (6 total), please visit the HSDB record page.

12.1.6 Non-Human Toxicity Values

LD50 rat (young) oral 4900 mg/kg bw
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. V12 101 (1976)
LD50 Rat oral 1900 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. 1622
LD50 rat oral 3200 mg/kg bw
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. V12 101 (1976)

12.1.7 Ongoing Test Status

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 June 21, 2012: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=150-69-6]

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

The only known use of dulcin was as a non-nutritive sweetner which is now banned in most countries. Dulcin's production and former use as a sweetener may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 9.8X10-6 mm Hg at 25 °C indicates dulcin will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase dulcin 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 9 hours. Particulate-phase dulcin will be removed from the atmosphere by wet or dry deposition. Dulcin absorbs light in the environmental UV spectrum and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, dulcin is expected to have very high mobility based upon an estimated Koc value of 43. The estimated Koc value for dulcin, which is a phenylurea compound, are consistent with observed Koc values for similar phenylurea compounds and herbicides which have Koc values in the in range of 20 to 75. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.58X10-11 atm-cu m/mole. Dulcin is not expected to volatilize from dry soil surfaces based upon its estimated vapor pressure. Phenylurea herbicides (similar in structure to dulcin) have reported soil dissipation half-lives on the order of 10 to 100 days with an approximate median soil dissipation half-life of 30 to 60 days; the soil dissipation rate of dulcin may be similar. If released into water, dulcin is not expected to adsorb to suspended solids and sediment based upon the estimated Koc value. 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 half-lives at environmental pHs are expected to be on the order of 1 year or more. Occupational exposure to dulcin may occur through dermal contact with this compound at workplaces where dulcin is produced or used. Monitoring data were not available to indicate how the general population might be exposed to dulcin; however, dulcin's former use as sweetener (used in combination with saccharin) would have exposed the general population through ingestion of food and beverages containing the compound. (SRC)

12.2.2 Natural Pollution Sources

Dulcin is not known to occur as a natural product(1).
(1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, International Agency For Research on Cancer, 1972-Present (Multi-volume work), V12: 97-105 (1976)

12.2.3 Artificial Pollution Sources

The only known use of dulcin was as a non-nutritive sweetner(1); use as sweetner is now banned in most countries(2). Dulcin's production and former use as a sweetner(1,2) may result in its release to the environment through various waste streams(SRC).
(1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, International Agency For Research on Cancer, 1972-Present (Multi-volume work), V12: 97-105 (1976)
(2) von Rymon Lipinski,GW; Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2012). New York, NY: John Wiley & Sons; Sweetners. Online Posting Date: June 15, 2000

12.2.4 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 43(SRC), determined from a structure estimation method(2), indicates that dulcin is expected to have very high mobility in soil(SRC). The estimated Koc value for dulcin, which is a phenylurea compound, are consistent with observed Koc values for phenylurea compounds and herbicides such as phenylurea, tolylurea, chlorophenylurea, fenuron, fluometuron, methoxyphenylurea, metoxuron and others(SRC) which have Koc values in the in range of 20 to 75(3). Volatilization of dulcin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.58X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Dulcin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Phenylurea herbicides (such as linuron, metoxuron, fluometuron, siduron, monolinuron, isoproturon and chlorotoluron) have reported soil dissipation half-lives on the order of 10 to 100 days(4) with an approximate median soil dissipation half-life of 30 to 60 days(SRC); the soil dissipation rate of dulcin may be similar(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2011. Available from, as of June 28, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Schuurmann G et al; Environ Sci Technol 40: 7005-7011 (2006)
(4) MacBean C, ed; e-Pesticide Manual. 15th ed., ver. 5.1, Alton, UK; British Crop Protection Council, (2008-2010)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 43(SRC), determined from a structure estimation method(2), indicates that dulcin is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.58X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 3(SRC), from its estimated log Kow and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Ureas with chemical structures similar to dulcin have observed aqueous hydrolysis half-lives on the order of one year or more at environmental pHs(2). Dulcin has a UV absorption max at 290 nm(5) which indicates it may be susceptible to direct photolysis by sunlight(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2011. Available from, as of June 28, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, International Agency For Research on Cancer, 1972-Present (Multi-volume work), V12: 97-105 (1976)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dulcin, which has an estimated vapor pressure of 9.8X10-6 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 dulcin 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 9 hours(SRC), calculated from its rate constant of 4.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase dulcin may be removed from the air by wet or dry deposition(SRC). Dulcin has a UV absorption max at 290 nm(3) which indicates it 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. Jan, 2011. Available from, as of June 28, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, International Agency For Research on Cancer, 1972-Present (Multi-volume work), V12: 97-105 (1976)

12.2.5 Environmental Biodegradation

AEROBIC: In Warburg respirometer studies using activated sludge inoculum at 2500 mg/L from three sewage treatment plants in Tennessee and a 144-hour incubation period, dulcin (present at 500 mg/L) was found to be toxic (inhibitory or lethal to sludge organisms) using Ashland City sludge(1); using Nashville sludge, theoretical oxygen demand ranged from 1.9-13.0%(1); using Franklin City sludge, theoretical oxygen demand ranged from 5.8-24.2%(1).
(1) Malaney GW et al; J Water Pollut Control Fed 39: 2020-202 (1967)

12.2.6 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of dulcin with photochemically-produced hydroxyl radicals has been estimated as 4.4X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 9 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Ureas with chemical structures similar to dulcin have observed aqueous hydrolysis half-lives on the order of one year or more at environmental pHs(1). Dulcin has a UV absorption max at 290 nm(2) which indicates it may be susceptible to direct photolysis by sunlight(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2011. Available from, as of June 28, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, International Agency For Research on Cancer, 1972-Present (Multi-volume work), V12: 97-105 (1976)

12.2.7 Environmental Bioconcentration

An estimated BCF of 3 was calculated in fish for dulcin(SRC), using an estimated log Kow of 1.28(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2011. Available from, as of June 28, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.8 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of dulcin can be estimated to be 43(SRC). According to a classification scheme(2), this estimated Koc value suggest that dulcin is expected to have very high mobility in soil. The estimated Koc value for dulcin, which is a phenylurea compound, are consistent with observed Koc values for phenylurea compounds and herbicides such as phenylurea, tolylurea, chlorophenylurea, fenuron, fluometuron, methoxyphenylurea, metoxuron and others(SRC) which have Koc values in the in range of 20 to 75(3).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2011. Available from, as of June 28, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Schuurmann G et al; Environ Sci Technol 40: 7005-7011 (2006)

12.2.9 Volatilization from Water / Soil

The Henry's Law constant for dulcin is estimated as 1.58X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that dulcin is expected to be essentially nonvolatile from water surfaces(2). Dulcin's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Dulcin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(1).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2011. Available from, as of June 28, 2012: 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. 15-1 to 15-29 (1990)

12.2.10 Probable Routes of Human Exposure

Occupational exposure to dulcin may occur through dermal contact with this compound at workplaces where dulcin is produced or used(SRC). Monitoring data were not available to indicate how the general population might be exposed to dulcin(SRC); however, dulcin's former use as sweetner (used in combination with saccharin)(1) would have exposed the general population through ingestion of food and beverages containing the compound(SRC).
(1) von Rymon Lipinski,GW; Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2012). New York, NY: John Wiley & Sons; Sweetners. Online Posting Date: June 15, 2000

13 Literature

13.1 Consolidated References

552 items
Page of 111

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

484 items
Page of 97

13.4 Chemical Co-Occurrences in Literature

Chemical
Selected evidence
363 articles
View All
Chemical
Selected evidence
177 articles
View All
Chemical
Selected evidence
115 articles
View All

13.5 Chemical-Gene Co-Occurrences in Literature

Gene/Protein/Enzyme
Selected evidence
4 articles
View All
Gene/Protein/Enzyme
Selected evidence
3 articles
View All
Gene/Protein/Enzyme
Selected evidence
3 articles
View All

13.6 Chemical-Disease Co-Occurrences in Literature

Disease
Selected evidence
1 article
View All
Disease
Selected evidence
1 article
View All
Disease
Selected evidence
1 article
View All

13.7 Chemical-Organism Co-Occurrences in Literature

Organism
Selected evidence
4 articles
View All
Organism
Selected evidence
1 article
View All
Organism
Selected evidence
2 articles
View All

14 Patents

14.1 Depositor-Supplied Patent Identifiers

6,091 items
Page of 1,219

14.2 WIPO PATENTSCOPE

14.3 Chemical Co-Occurrences in Patents

14.4 Chemical-Disease Co-Occurrences in Patents

Disease
Selected evidence
145 patents from 113 patent families
View All

14.5 Chemical-Gene Co-Occurrences in Patents

14.6 Chemical-Organism Co-Occurrences in Patents

Organism
Selected evidence
504 patents from 381 patent families
View All
Organism
Selected evidence
359 patents from 276 patent families
View All

15 Interactions and Pathways

15.1 Chemical-Target Interactions

1 item
Gene
Taxonomy
Action
GNAT3 protein affects the susceptibility to dulcin
Evidence IDs
Data Source

16 Biological Test Results

16.1 BioAssay Results

1,264 items
Page of 253

17 Classification

17.1 MeSH Tree

  • structure
    MeSH Concept: M0045381
    MeSH Descriptor: C004352

17.2 ChEBI Ontology

17.3 ChemIDplus

  • CAMEO
    Computer-Aided Management of Emergency Operation - CAMEO Chemicals is a library of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States
  • CCRIS
    Chemical Carcinogenesis Research Information System - Carcinogenicity, mutagenicity, tumor promotion and tumor inhibition data from the National Cancer Institute (NCI). CCRIS provides historical information from the years 1985 - 2011. It is no longer updated.
  • CTD
    Comparative Toxicogenomics Database - CTD selects and organizes gene, sequence, chemical, reference, and taxonomic data about gene-chemical interactions. It is hosted at North Carolina State University (NCSU).
  • ChEBI
    Chemical Entities of Biological Interest - Dictionary of molecular entities focused on "small" chemical compounds. ChEBI is part of the EMBL-European Bioinformatics Institute.
  • DrugPortal
    Drug Information Portal - Portal to selected drug information from the U.S. National Library of Medicine and other key U.S. Government agencies
Page of 6

17.4 CAMEO Chemicals

  • Reactive group: Amides and Imides
  • Reactive group: Amines, Aromatic

17.5 UN GHS Classification

  • H302: Harmful if swallowed [Warning Acute toxicity, oral]
  • H315: Causes skin irritation [Warning Skin corrosion/irritation]
  • H319: Causes serious eye irritation [Warning Serious eye damage/eye irritation]
  • Acute toxicity, oral
  • Serious eye damage/eye irritation
Page of 4

17.6 NORMAN Suspect List Exchange Classification

  • A 2017 list of REACH chemicals including InChIKeys and spectral information, provided by N. Alygizakis and J. Slobodnik, EI. Dataset DOI:10.5281/zenodo.2653020
  • HBM4EU CECscreen is a suspect screening list for Chemicals of Emerging Concern (CECs) plus metadata and predicted Phase 1 metabolites; this list contains the CECs only. CECScreen is part of the HBM4EU project (coord. UBA) > WP16 emerging chemicals (lead INRA, JP Antignac/L Debrauwer) > Task 16.1 (lead IRAS, J Vlanderen / R Vermeulen) > Main contributor (J Meijer) > Involved Partners (M Lamoree, T Hamers, S Hutinet, A, Covaci, C Huber, M Krauss, DI Walker, EL Schymanski). Further details in Meijer et al (2021) DOI:10.1016/j.envint.2021.106511. Dataset DOI:10.5281/zenodo.3956586
  • The Food Contact Chemicals database (FCCdb, DOI:10.5281/zenodo.3240108) is a compilation of information on over 12,000 intentionally added food contact chemicals extracted from publicly available sources such as legislation or industry inventories for different types of food contact materials and selected sources of hazard information, as described by Groh et al. 2021 (see DOI:10.1016/j.envint.2020.106225). Structural information for ~6000 entries where clear mappings could be found was added by P. Chirsir into FCCdb Version 5, prior to hosting it on the NORMAN Suspect List Exchange (see Dataset DOI:10.5281/zenodo.4625495). Further detailed descriptions for each sub-category in the classification tree can be found in the ReadMe tab of the FCCdb spreadsheet file, or in the respective sub-category tooltips ('?' boxes).
  • List of chemicals on the market from the Swedish Chemicals Agency (KEMI). Provided by Stellan Fischer, KEMI including Hazard and Exposure scores. Curated by Reza Aalizadeh, University of Athens. Dataset DOI:10.5281/zenodo.2628786
  • The Wiley Registry of Tandem Mass Spectral Data, MSforID contains high-quality tandem MS acquired on a QqTOF instrument, developed by Herbert Oberacher (Medical University of Innsbruck, Austria). More information at www.msforid.com. Dataset DOI:10.5281/zenodo.2653016
Page of 3

17.7 EPA DSSTox Classification

Page of 11

17.8 International Agency for Research on Cancer (IARC) Classification

  • Group 3: Not classifiable as to its carcinogenicity to humans
    This category is used most commonly when the evidence of carcinogenicity in humans is inadequate, the evidence of carcinogenicity in experimental animals is limited (or inadequate), and the mechanistic evidence is limited (or inadequate). Limited evidence of carcinogenicity in experimental animals means that the available information suggests a carcinogenic effect but is not conclusive.

17.9 EPA Substance Registry Services Tree

  • CAMEO Chemicals
    CAMEO Chemicals is an emergency response and planning tool. This program includes an extensive chemical database with critical response information for thousands of chemicals, as well as a reactivity prediction tool that allows you to see what hazards might occur if chemicals in your collection were mixed together. CAMEO Chemicals is available as a website, mobile website, and a desktop application. CAMEO Chemicals is part of a software suite of programs called CAMEO (Computer-Aided Management of Emergency Operations). The CAMEO suite also includes a hazard modeling tool (ALOHA), a mapping program (MARPLOT), and two database applications (CAMEOfm and Tier2 Submit) designed to assist with the data management requirements under the Emergency Planning and Community Right-to-Know Act (EPCRA, also known as SARA Title III). The CAMEO suite programs can be used (individually or together) to help first responders and emergency planners access and manage crucial chemical property and emergency response information for hazardous chemical releases. The CAMEO programs are developed jointly by EPAÂ’s Office of Emergency Management and NOAAÂ’s Office of Response and Restoration.
  • Ecotoxicology Database
    ECOTOX :: Comprehensive database providing adverse effects of single chemical stressors to ecologically relevent aquatic and terrestrial species.
  • ICIS-Air
    ICIS-Air manages stationary source air program compliance and enforcement information. The data stored in ICIS-Air are primarily collected by State and local agencies and submitted to ICIS-Air as required by rule. The data stored in ICIS-Air are needed by EPA and state/local air agencies to carry out air program compliance management.
  • Chemical Abstracts Index Name
    CA Index :: The Chemical Abstracts Services (CAS) Registry File is a chemical structure and dictionary database containing unique records for chemical substances that have been published. All substance records are assigned a unique CAS Registry Number and a Chemical Abstracts (CA) index name. The records may also contain additional information, such as other names, molecular formulas, and structure diagrams related to the specific substance. The CA Index name is used as the name source in CRS when an 8th or 9th CI name is not available.
  • Chemical Identification
    ChemIDStd :: The Chemical Identification Data Standard was developed by a Chemical Data Standard Work Group comprised of representatives from across U.S. EPA programs. The consensus standard defines what information is required to identify a chemical substance and how that information should be recorded. The Chemical Identification Data Standard provides for the use of 4 specific identifiers for chemical substances in the Substance Registry System: the Chemical Abstracts Service Registry Number (CASRN) - the unique number assigned by Chemical Abstracts Service (CAS) to a chemical substance; the Chemical Substance Systematic Name - the name assigned to a chemical substance that describes it in terms of its molecular composition; the EPA Chemical Internal Tracking Number - the unique record number assigned to all chemical substances and chemical groupings for internal tracking within EPA systems; and the EPA Chemical Registry Name - the name EPA has selected as the name to be commonly used by EPA in referring to a chemical substance.
Page of 2

17.10 CCS Classification - Baker Lab

  • [M+H]+
  • [M+Na]+

17.11 MolGenie Organic Chemistry Ontology

  • aryl alkyl ethers
  • aromatic compounds
    compounds containing any aromatic carbon or other aromatic atoms.
  • drug like compounds
    Using a Fragment Based Druglikeness from OpenChemLib > -1
  • aromatic compounds
    compounds containing any aromatic carbon or other aromatic atoms.
  • anilines
Page of 8

18 Information Sources

  1. Baker Lab, Chemistry Department, The University of North Carolina at Chapel Hill
    Dulcin
    CCS Classification - Baker Lab
    https://tarheels.live/bakerlab/
  2. CAMEO Chemicals
    LICENSE
    CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data.
    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
    CAMEO Chemical Reactivity Classification
    https://cameochemicals.noaa.gov/browse/react
  3. 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/
  4. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/chemidplus
  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 DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  7. 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
  8. 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
  9. Hazardous Substances Data Bank (HSDB)
  10. 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
  11. ChEBI
  12. 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
  13. 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
  14. FDA Substances Added to Food
    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
  15. 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/
    Dulcin
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  16. MassBank Europe
  17. 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/
  18. Japan Chemical Substance Dictionary (Nikkaji)
  19. Joint FAO/WHO Expert Committee on Food Additives (JECFA)
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) licence.
    https://www.who.int/about/policies/publishing/copyright
  20. 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
  21. 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
  22. Metabolomics Workbench
  23. 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
    Urea, (4-ethoxyphenyl)-
    http://www.nist.gov/srd/nist1a.cfm
  24. SpectraBase
  25. Springer Nature
  26. Wikidata
  27. Wikipedia
  28. 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
  29. PubChem
  30. GHS Classification (UNECE)
  31. EPA Substance Registry Services
    EPA SRS List Classification
    https://maldi.nist.gov
  32. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  33. PATENTSCOPE (WIPO)
  34. NCBI
CONTENTS