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Estradiol

PubChem CID
5757
Structure
Estradiol_small.png
Estradiol_3D_Structure.png
Molecular Formula
Synonyms
  • estradiol
  • beta-Estradiol
  • 17beta-Estradiol
  • 50-28-2
  • Oestradiol
Molecular Weight
272.4 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2004-09-16
  • Modify:
    2025-01-18
Description
17beta-estradiol is the 17beta-isomer of estradiol. It has a role as an estrogen, a human metabolite, an EC 1.2.3.1 (aldehyde oxidase) inhibitor, a Daphnia magna metabolite, a mouse metabolite and a geroprotector. It is a 17beta-hydroxy steroid and an estradiol.
Estradiol is a naturally occurring hormone circulating endogenously in females. It is commercially available in several hormone therapy products for managing conditions associated with reduced estrogen, such as vulvovaginal atrophy and hot flashes. Some available forms of estradiol include oral tablets, injections, vaginal rings, transdermal patches, sprays, gels, and creams. When used for oral or IM administration, estradiol is commonly synthesized as a pro-drug ester (such as [DB13952], [DB13953], [DB13954], [DB13955], and [DB13956]). Because it has a low oral bioavailability on its own, estradiol is commonly formulated with an ester side-chain. [DB00977] (EE) is a synthetic form of estradiol commonly used as the estrogenic component of most combination oral contraceptive pills (OCPs). Ethinyl estradiol is different from estradiol due to its higher biovailability and increased resistance to metabolism, rendering it more suitable for oral administration.
Estradiol is an Estrogen. The mechanism of action of estradiol is as an Estrogen Receptor Agonist.
See also: Estradiol Valerate (active moiety of); Estradiol Benzoate (active moiety of); Estradiol Cypionate (active moiety of) ... View More ...

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Estradiol.png

1.2 3D Conformer

1.3 Crystal Structures

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C18H24O2/c1-18-9-8-14-13-5-3-12(19)10-11(13)2-4-15(14)16(18)6-7-17(18)20/h3,5,10,14-17,19-20H,2,4,6-9H2,1H3/t14-,15-,16+,17+,18+/m1/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

VOXZDWNPVJITMN-ZBRFXRBCSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CCC4=C3C=CC(=C4)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C18H24O2
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

50-28-2

2.3.2 Deprecated CAS

1050677-52-5, 1206475-11-7, 873662-39-6
1050677-52-5, 1206475-11-7

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 Lipid Maps ID (LM_ID)

2.3.12 Metabolomics Workbench ID

2.3.13 NCI Thesaurus Code

2.3.14 Nikkaji Number

2.3.15 NSC Number

2.3.16 PharmGKB ID

2.3.17 Pharos Ligand ID

2.3.18 RXCUI

2.3.19 Wikidata

2.3.20 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 17 beta Estradiol
  • 17 beta Oestradiol
  • 17 beta-Estradiol
  • 17 beta-Oestradiol
  • Aerodiol
  • Delestrogen
  • Estrace
  • Estraderm TTS
  • Estradiol
  • Estradiol 17 alpha
  • Estradiol 17 beta
  • Estradiol 17beta
  • Estradiol Anhydrous
  • Estradiol Hemihydrate
  • Estradiol Hemihydrate, (17 alpha)-Isomer
  • Estradiol Monohydrate
  • estradiol valerate
  • estradiol valeriante
  • Estradiol, (+-)-Isomer
  • Estradiol, (-)-Isomer
  • Estradiol, (16 alpha,17 alpha)-Isomer
  • Estradiol, (16 alpha,17 beta)-Isomer
  • Estradiol, (17-alpha)-Isomer
  • Estradiol, (8 alpha,17 beta)-(+-)-Isomer
  • Estradiol, (8 alpha,17 beta)-Isomer
  • Estradiol, (9 beta,17 alpha)-Isomer
  • Estradiol, (9 beta,17 beta)-Isomer
  • Estradiol, Monosodium Salt
  • Estradiol, Sodium Salt
  • Estradiol-17 alpha
  • Estradiol-17 beta
  • Estradiol-17beta
  • Oestradiol
  • Ovocyclin
  • Progynon Depot
  • Progynon-Depot
  • Progynova
  • Vivelle

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
272.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
4
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
272.177630004 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
272.177630004 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
40.5 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
20
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
382
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
5
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

Solid
White powder.

3.2.2 Color / Form

White crystalline powder. Prisms from 80% 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. 635
White or slightly yellow, small crystals or crystalline powder
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512

3.2.3 Odor

Odorless
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512

3.2.4 Boiling Point

445.9±45.0

3.2.5 Melting Point

173
178.5 °C
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-230
178-179 °C

3.2.6 Solubility

3.6 mg/L (at 27 °C)
YALKOWSKY,SH & DANNENFELSER,RM (1992)
Very soluble in acetone, ethanol, dioxane
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-230
Freely soluble in alcohol; soluble in acetone, dioxane, other organic solvents; solutions of fixed alkali hydroxides; sparingly soluble in vegetable oils.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 635
In water, 3.90 mg/L at 27 °C
Yalkowsky, S.H., He, Yan., Handbook of Aqueous Solubility Data: An Extensive Compilation of Aqueous Solubility Data for Organic Compounds Extracted from the AQUASOL dATAbASE. CRC Press LLC, Boca Raton, FL. 2003., p. 1111
0.0036 mg/mL

3.2.7 LogP

4.01
HANSCH,C ET AL. (1995)
log Kow = 4.01 /B-estradiol/
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 158
4.01
HANSCH,C ET AL. (1995)

3.2.8 Optical Rotation

Crystals from alcohol, mp 191-196 °C. Stable in air. Specific optical rotation: +58 deg at 25 °C/D to +63 deg at 25 °C/D (c = 2 in dioxane). Soluble in alcohol, acetone, dioxane; slightly soluble in ether, vegetable oils. /Estradiol 3-benzoate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 635
Crystals from benzene + petroleum ether, mp 151-152 °C. Specific optical rotation: +45 deg at 25 °C/D (chloroform). Soluble in ether, methanol, benzene, chloroform, peanut oil, cottonseed oil, corn oil, sesame oil. /Estradiol 17 beta-cyclopentanepropanoate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 635
Specific optical rotation at 25 °C for D (sodium) line: +76 deg at 25 °C/D to +83 deg at 25 °C/D (dioxane)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 635

3.2.9 Decomposition

When heated to decomposition it emits acrid smoke and irritating fumes.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1600

3.2.10 Caco2 Permeability

-4.77
ADME Research, USCD

3.2.11 Dissociation Constants

pKa
10.46±0.03
Profiles of Drug Substances, Excipients and Related Methodology Volume 33

3.2.12 Collision Cross Section

173.34 Ų [M-H]- [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

159.7 Ų [M+H-H2O]+ [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

156.66 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

162.82 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

161.04 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

158.2 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.13 Other Experimental Properties

It occurs in two isomeric forms, alpha and beta. Beta-estradiol has the greatest physiological activity of any naturally occurring estrogen. The alpha-form is relatively inactive.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512
Stable in air
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512
Precipitated by digitonin; stable in 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. 635
Crystals, mp 144-145 °C /Estradiol 17-valerate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 635
For more Other Experimental Properties (Complete) data for ESTRADIOL (6 total), please visit the HSDB record page.

3.3 Chemical Classes

Hormone and(or) waste-water effluent contaminant

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceutical
S120 | DUSTCT2024 | Substances from Second NORMAN Collaborative Dust Trial | DOI:10.5281/zenodo.13835254
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Estrogens; Hormones
Human drug -> Prescription; Discontinued
Human drug -> Discontinued
Human drug -> Prescription
Human drug -> Prescription; Discontinued; Active ingredient (ESTRADIOL)
3.3.1.2 Animal Drugs
Active Ingredients (Estradiol) -> FDA Greenbook
Pharmaceuticals -> Animal Drugs -> Approved in Taiwan
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

3.3.2 Endocrine Disruptors

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

3.3.3 Lipids

Lipids -> Sterol Lipids [ST] -> Steroids [ST02] -> C18 steroids (estrogens) and derivatives [ST0201]

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 1H NMR Spectra

1 of 3
View All
Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
100%_DMSO
pH
7.00
Shifts [ppm]:Intensity
1.36:2.34, 1.27:8.31, 2.69:7.23, 1.75:3.81, 1.89:1.61, 1.21:4.75, 2.04:3.05, 1.76:3.55, 1.13:2.20, 2.71:3.89, 1.78:3.86, 1.29:9.18, 2.23:2.54, 1.08:3.05, 1.37:3.43, 1.16:5.19, 2.72:4.09, 1.23:6.15, 1.86:3.40, 1.35:2.28, 2.05:4.83, 1.18:3.70, 2.67:1.85, 1.56:2.35, 0.66:100.00, 6.43:15.89, 2.68:6.42, 2.74:0.96, 1.84:6.27, 1.19:1.85, 1.24:4.68, 1.12:4.16, 1.11:4.48, 1.55:1.77, 3.51:10.45, 2.06:5.19, 1.85:2.24, 1.57:3.72, 6.42:15.30, 1.20:4.27, 1.58:3.82, 7.03:13.35, 1.20:2.68, 6.49:7.54, 1.75:3.48, 1.88:3.57, 1.33:1.69, 2.24:3.72, 1.82:6.42, 1.16:5.30, 1.60:1.52, 1.40:1.64, 1.84:4.93, 2.73:1.08, 7.04:12.72, 2.75:0.97, 1.55:2.00, 6.49:8.44, 2.03:2.65, 1.82:4.37, 1.40:1.49, 2.69:9.69, 1.83:4.29, 6.51:7.80, 1.76:4.23, 1.38:4.23, 1.23:6.49, 2.08:2.61, 1.78:3.77, 1.34:2.10, 1.07:2.40, 1.89:2.94, 1.58:3.48, 1.31:5.40, 1.39:1.82, 1.25:6.18, 1.22:6.02, 2.07:2.77, 1.38:3.37, 1.88:3.79, 1.81:3.73, 1.09:4.57, 1.22:6.12, 2.22:4.16, 1.87:3.83, 1.91:1.27, 2.22:2.50, 1.27:9.26, 1.31:4.33, 1.77:4.03, 6.50:8.86, 1.57:4.03, 1.36:4.40, 1.18:3.88, 1.25:6.97, 2.23:4.11, 2.21:4.11, 1.34:1.64, 2.66:1.39, 1.10:4.78, 1.58:3.51, 1.14:2.50, 1.59:2.13
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2 of 3
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Instrument Name
Varian CFT-20
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
Schering Corporation, Bloomfield, New Jersey
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 2D NMR Spectra

4.2.1 1H-13C NMR Spectra

2D NMR Spectra Type
1H-13C HSQC
Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
100%_DMSO
pH
7.00
Shifts [ppm] (F2:F1):Intensity
1.30:25.91:0.10, 2.50:39.52:0.54, 7.04:125.84:0.69, 1.16:36.53:0.24, 6.43:114.57:1.00, 0.66:11.01:0.10, 1.88:29.70:0.21, 2.22:25.91:0.19, 1.83:36.53:0.19, 2.69:28.89:0.65, 3.51:79.71:0.50, 1.28:38.53:0.14, 1.37:29.70:0.16, 2.06:43.50:0.34, 1.24:22.59:0.13, 1.10:49.48:0.25, 1.77:26.90:0.22, 1.58:22.59:0.25, 6.50:112.55:0.65, 1.22:26.90:0.13
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4.3 Mass Spectrometry

4.3.1 GC-MS

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

272.0 99.99

213.0 29.20

146.0 23.30

172.0 22.70

273.0 20.70

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Notes
instrument=JEOL JMS-01-SG-2
2 of 16
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Spectra ID
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

272.0 99.99

160.0 39.80

18.0 33

172.0 30.70

133.0 24.80

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Notes
instrument=HITACHI RMU-6E

4.3.2 MS-MS

1 of 8
View All
Spectra ID
Ionization Mode
Negative
Top 5 Peaks
271.1707 100
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2 of 8
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

109.0645 100

83.049 29.02

100.0756 8.28

145.1014 8.19

107.0852 7.21

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4.3.3 LC-MS

1 of 18
View All
Authors
da Silva KM, Iturrospe E, van de Lavoir M, Robeyns R, University of Antwerp, Belgium
Instrument
Agilent 6560 QTOF
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
NEGATIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Retention Time
0.214 min
Precursor m/z
271.1704
Precursor Adduct
[M-H]-
Top 5 Peaks
271.1689 999
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License
CC BY
2 of 18
View All
Authors
da Silva KM, Iturrospe E, van de Lavoir M, Robeyns R, University of Antwerp, Belgium
Instrument
Agilent 6560 QTOF
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
NEGATIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Retention Time
0.190 min
Precursor m/z
271.1704
Precursor Adduct
[M-H]-
Top 5 Peaks

271.1689 999

123.0821 53

183.08 44

142.0394 40

239.1401 17

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License
CC BY

4.3.4 Other MS

1 of 8
View All
Other MS
MASS: 62029 (NITS/EPA/MSDC Mass Spectral Database, 1990 version)
2 of 8
View All
Authors
KOGA M, UNIV. OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH
Instrument
JEOL JMS-01-SG-2
Instrument Type
EI-B
MS Level
MS
Ionization Mode
POSITIVE
Ionization
ENERGY 75 eV
Top 5 Peaks

272 999

213 292

146 233

172 227

273 207

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License
CC BY-NC-SA

4.4 UV Spectra

UV max: 225, 280 nm
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 635

4.5 IR Spectra

IR Spectra
IR: 5498 (Coblentz Society spectral collection)

4.5.1 FTIR Spectra

1 of 2
Technique
KBr WAFER
Source of Sample
SCHERING CORPORATION, BLOOMFIELD, NEW JERSEY
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Instrument Name
Bio-Rad FTS
Technique
KBr1 0.68mg
Source of Spectrum
Forensic Spectral Research
Source of Sample
Steraloids
Catalog Number
E0950-000
Lot Number
B0145
Copyright
Copyright © 2008-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.5.2 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Steraloids Inc.
Catalog Number
E0950-000
Lot Number
B0145
Copyright
Copyright © 2009-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.6 Raman Spectra

1 of 2
Technique
FT-Raman
Source of Spectrum
Forensic Spectral Research
Source of Sample
Steraloids Inc.
Catalog Number
E0950-000
Lot Number
B0145
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Catalog Number
250155
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

Estradiol is indicated in various preparations for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of postmenopausal osteoporosis. It is also used for the treatment of breast cancer (only for palliation therapy) in certain men or women with metastatic disease, and for the treatment of androgen-dependent prostate cancer (only for palliation therapy). It is also used in combination with other hormones as a component of oral contraceptive pills for preventing pregnancy (most commonly as [DB00977], a synthetic form of estradiol). **A note on duration of treatment** Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as concerns were raised regarding estrogen use. Specifically, the combined estrogen–progestin group was discontinued after about 5 years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events. Following extensive critique of the WHI results, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years postmenopause) in low doses, and in women without a history of breast cancer or increased risk of cardiovascular or thromboembolic disease. Estrogen for postmenopausal symptoms should always be given with a progestin component due to estrogen's stimulatory effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer over the long-term.

7.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Estrogens; Hormones

7.3 FDA Approved Drugs

7.4 FDA Orange Book

7.5 FDA National Drug Code Directory

7.6 FDA Green Book

7.7 Drug Labels

Drug and label
Active ingredient and drug
Homeopathic product and label
Homeopathic product and label

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.8.3 NIPH Clinical Trials Search of Japan

7.9 Therapeutic Uses

Estradiol tablets are indicated in the treatment of moderate to severe vasomotor symptoms associated with the menopause. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
Estradiol tablets are indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
Estradiol tablets are indicated in the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
Estradiol tablets are indicated in the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
For more Therapeutic Uses (Complete) data for ESTRADIOL (7 total), please visit the HSDB record page.

7.10 Drug Warnings

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER- Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than "synthetic" estrogens at equivalent estrogen doses.
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
CARDIOVASCULAR AND OTHER RISKS- Estrogens with or without progestins should not be used for the prevention of cardiovascular disease.
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo.
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy.
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
For more Drug Warnings (Complete) data for ESTRADIOL (48 total), please visit the HSDB record page.

7.11 Biomarker Information

8 Food Additives and Ingredients

8.1 Food Additive Classes

JECFA Functional Classes
Veterinary Drug -> PRODUCTION_AID;

8.2 Associated Foods

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

Chemical Name
ESTRADIOL-17BETA
Evaluation Year
2000
ADI
0-50 ng/kg bw
Comments
The Committee established an ADI of 0-50 ng/kg bw on the basis of the NOEL of 0.3 mg/day (5 µg/kg bw/day) in studies of changes in several hormone-dependent parameters in postmenopausal women. A safety factor of 10 was used to account for normal variation among individuals, and an additional factor of 10 was added to protect sensitive populations. Based on a calculated range of excess intake of total estrogens of 30-50 ng/p/d (< 2% of ADI), the Committee concluded that there was no need to specify MRL values when the drug was used in accordance with good veterinary practices.
Tox Monograph

9 Pharmacology and Biochemistry

9.1 Pharmacodynamics

Estradiol acts on the on the estrogen receptors to relieve vasomotor systems (such as hot flashes) and urogenital symptoms (such as vaginal dryness and dyspareunia). Estradiol has also been shown to exert favorable effects on bone density by inhibiting bone resorption. Estrogen appears to inhibit bone resorption and may have beneficial effects on the plasma lipid profile. Estrogens cause an increase in hepatic synthesis of various proteins, which include sex hormone binding globulin (SHBG), and thyroid-binding globulin (TBG). Estrogens are known to suppress the formation of follicle-stimulating hormone (FSH) in the anterior pituitary gland. **A note on hyper-coagulable state, cardiovascular health, and blood pressure** Estradiol may cause an increased risk of cardiovascular disease, DVT, and stroke, and its use should be avoided in patients at high risk of these conditions. Estrogen induces a hyper-coagulable state, which is also associated with both estrogen-containing oral contraceptive (OC) use and pregnancy. Although estrogen causes an increase in levels of plasma renin and angiotensin. Estrogen-induced increases in angiotensin, causing sodium retention, which is likely to be the mechanism causing hypertension after oral contraceptive treatment.

9.2 MeSH Pharmacological Classification

Estrogens
Compounds that interact with ESTROGEN RECEPTORS in target tissues to bring about the effects similar to those of ESTRADIOL. Estrogens stimulate the female reproductive organs, and the development of secondary female SEX CHARACTERISTICS. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. (See all compounds classified as Estrogens.)

9.3 FDA Pharmacological Classification

1 of 4
FDA UNII
4TI98Z838E
Active Moiety
ESTRADIOL
Pharmacological Classes
Chemical Structure [CS] - Estradiol Congeners
Pharmacological Classes
Established Pharmacologic Class [EPC] - Estrogen
Pharmacological Classes
Mechanisms of Action [MoA] - Estrogen Receptor Agonists
FDA Pharmacology Summary
Estradiol is an Estrogen. The mechanism of action of estradiol is as an Estrogen Receptor Agonist.
2 of 4
Non-Proprietary Name
ESTRADIOL
Pharmacological Classes
Estrogen [EPC]; Estrogen Receptor Agonists [MoA]; Estradiol Congeners [CS]
3 of 4
Non-Proprietary Name
ESTRADIOL GEL 0.1%
Pharmacological Classes
Estradiol Congeners [CS]; Estrogen Receptor Agonists [MoA]; Estrogen [EPC]
4 of 4
Non-Proprietary Name
ESTRADIOL,
Pharmacological Classes
Estrogen [EPC]; Estrogen Receptor Agonists [MoA]; Estradiol Congeners [CS]

9.4 ATC Code

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

G - Genito urinary system and sex hormones

G03 - Sex hormones and modulators of the genital system

G03C - Estrogens

G03CA - Natural and semisynthetic estrogens, plain

G03CA03 - Estradiol

9.5 Absorption, Distribution and Excretion

Absorption
The absorption of several formulations of estradiol is described below: Oral tablets and injections First-pass metabolism in the gastrointestinal tract rapidly breaks down estradiol tablets before entering the systemic circulation. The bioavailability of oral estrogens is said to be 2-10% due to significant first-pass effects. The esterification of estradiol improves the administration (such as with estradiol valerate) or to sustain release from intramuscular depot injections (including estradiol cypionate) via higher lipophilicity. After absorption, the esters are cleaved, which leads to the release of endogenous estradiol, or 17β-estradiol. Transdermal preparations The transdermal preparations slowly release estradiol through intact skin, which sustains circulating levels of estradiol during a 1 week period of time. Notably, the bioavailability of estradiol after transdermal administration is about 20 times higher than after oral administration. Transdermal estradiol avoids first pass metabolism effects that reduce bioavailability. Administration via the buttock leads to a Cmax of about 174 pg/mL compared to 147 pg/mL via the abdomen. Spray preparations After daily administration, the spray formulations of estradiol reach steady state within 7-8 days. After 3 sprays daily, Cmax is about 54 pg/mL with a Tmax of 20 hours. AUC is about 471 pg•hr/mL. Vaginal ring and cream preparations Estradiol is efficiently absorbed through the mucous membranes of the vagina. The vaginal administration of estrogens evades first-pass metabolism. Tmax after vaginal ring delivery ranges from 0.5 to 1 hour. Cmax is about 63 pg/mL. The vaginal cream preparation has a Cmax of estradiol (a component of Premarin vaginal estrogen conjugate cream) was a Cmax of 12.8 ± 16.6 pg/mL, Tmax of 8.5 ± 6.2 hours, with an AUC of 231 ± 285 pg•hr/mL.
Route of Elimination
Estradiol is excreted in the urine with both glucuronide and sulfate conjugates.
Volume of Distribution
Estrogens administered exogenously distribute in a similar fashion to endogenous estrogens. They can be found throughout the body, especially in the sex hormone target organs, such as the breast, ovaries and uterus.
Clearance
In one pharmacokinetic study, the clearance of orally administered micronized estradiol in postmenopausal women was 29.9±15.5 mL/min/kg. Another study revealed a clearance of intravenously administered estradiol was 1.3 mL/min/kg.
Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.
US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686
The Estradiol Transdermal System Continuous Delivery (Once-Weekly) continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7 day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first-pass metabolism when estradiol is given by the transdermal route.
US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806

In a Phase I study of 14 postmenopausal women, the insertion of ESTRING (estradiol vaginal ring) rapidly increased serum estradiol (E2) levels. The time to attain peak serum estradiol levels (Tmax) was 0.5 to 1 hour. Peak serum estradiol concentrations post-initial burst declined rapidly over the next 24 hours and were virtually indistinguishable from the baseline mean (range: 5 to 22 pg/mL). Serum levels of estradiol and estrone (E1) over the following 12 weeks during which the ring was maintained in the vaginal vault remained relatively unchanged

Table: PHARMACOKINETIC MEAN ESTIMATES FOLLOWING SINGLE ESTRING APPLICATION

Estrogen
Estradiol (E2)
Cmax (pg/mL)
63.2
Css-48 hr (pg/mL)
11.2
Css-4weeks (pg/mL)
9.5
Css-12weeks (pg/mL)
8.0
Estrogen
Baseline-adjusted E2
Cmax (pg/mL)
55.6
Css-48 hr (pg/mL)
3.6
Css-4weeks (pg/mL)
2.0
Css-12weeks (pg/mL)
0.4
Estrogen
Estrone (E1)
Cmax (pg/mL)
66.3
Css-48 hr (pg/mL)
52.5
Css-4weeks (pg/mL)
43.8
Css-12weeks (pg/mL)
47.0
Estrogen
Baseline-adjusted E1
Cmax (pg/mL)
20.0
Css-48 hr (pg/mL)
6.2
Css-4weeks (pg/mL)
-2.4
Css-12weeks (pg/mL)
0.8

US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686
The initial estradiol peak post-application of the second ring in the same women resulted in ~38 percent lower Cmax, apparently due to reduced systemic absorption via the treated vaginal epithelium. The relative systemic exposure from the initial peak of ESTRING accounted for approximately 4 percent of the total estradiol exposure over the 12-week period.
US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686
For more Absorption, Distribution and Excretion (Complete) data for ESTRADIOL (17 total), please visit the HSDB record page.

9.6 Metabolism / Metabolites

Exogenously administered estrogens are metabolized in the same fashion as endogenous estrogens. Metabolic transformation occurs primarily in the liver and intestine. Estradiol is metabolized to estrone, and both are converted to estriol, which is later excreted in the urine. Sulfate and glucuronide conjugation estrogens also take place in the liver. Biliary secretion of metabolic conjugates are released into the intestine, and estrogen hydrolysis in the gut occurs, followed by reabsorption. The CYP3A4 hepatic cytochrome enzyme is heavily involved in the metabolism of estradiol. CYP1A2 also plays a role.
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006).
Variations in estradiol metabolism ... depend upon the stage of the menstrual cycle ... In general, the hormone undergoes rapid hepatic biotransformation with a plasma half-life measured in minutes.
Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1420
Estradiol is primarily converted ... to estriol, which is the major urinary metabolite. A variety of sulfate and glucuronide conjugates also are excreted in the urine.
Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1420
The metabolism of estradiol-17beta and estrone is similar in rats and in humans, in that both species transform these steroids mainly by (aromatic) 2-hydroxylation, and also by 16alpha-hydroxylation. Glucuronides of the various metabolites are excreted in the bile. Differences in the metabolism of estrogens by humans and rats lie mostly in the type of conjugation. A relatively large proportion of administered estrone, estradiol-17beta and estriol is transformed in rats to metabolites oxygenated both at C-2 and C-16. When estriol is administered to rats, glucuronides and, to a lesser extent, sulfates of 16-ketooestradiol and of 2- and 3-methyl ethers of 2-hydroxyoestriol and 2-hydroxy-16-ketooestradiol are excreted in the bile. In contrast, hydroxylations at C-6 or C-7 of ring B of estradiol-17beta and estrone are a minor pathway in rats. 2-Hydroxyoestrogens ('catechol estrogens') are further transformed by various routes, including covalent binding to proteins.
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. V21 307 (1979)
For more Metabolism/Metabolites (Complete) data for ESTRADIOL (8 total), please visit the HSDB record page.
17-beta-estradiol has known human metabolites that include 17-beta-Estradiol-3-glucuronide, 17-beta-Estradiol glucuronide, 2-hydroxyestradiol, and 4-Hydroxyestradiol.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450. Route of Elimination: Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Half Life: 36 hours

9.7 Biological Half-Life

The terminal half-lives for various estrogen products post oral or intravenous administration has been reported to range from 1-12 hours. One pharmacokinetic study of oral estradiol valerate administration in postmenopausal women revealed a terminal elimination half-life of 16.9 ± 6.0 h. A pharmacokinetic study of intravenous estradiol administration in postmenopausal women showed an elimination half-life of 27.45 ± 5.65 minutes. The half-life of estradiol appears to vary by route of administration.
... After oral administration ... the terminal half life was 20.1 hr ...
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. V72 476 (1999)

9.8 Mechanism of Action

Estrogen is found in the the breast, uterine, ovarian, skin, prostate, bone, fat, and brain tissues. The main source of estrogen in adult women during the reproductive period of life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day. After menopause, however, the majority of endogenous estrogen is produced by transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate, represent the most abundant estrogens found in postmenopausal women. Estradiol, however, is considerably more potent than estrone and estriol at the estrogen receptor (ER). As a result, the higher estrone concentration in postmenopausal population, can cause various undesirable effects. These effects may include hot flashes, chills, vaginal dryness, mood swings, irregular menstruation, and chills, in addition to sleep problems. Estradiol workings by binding to subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of this drug's rapid effects. Once the estrogen receptor has bound to its ligand, it enters the nucleus of the target cell, regulating gene transcription and formation of of messenger RNA. This mRNA makes contact with ribosomes producing specific proteins that express the effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a postmenopausal or low estradiol state.
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. ... After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485
Estrogens have an important role in the reproductive, skeletal, cardiovascular, and central nervous systems in women, and act principally by regulating gene expression. Biologic response is initiated when estrogen binds to a ligand-binding domain of the estrogen receptor resulting in a conformational change that leads to gene transcription through specific estrogen response elements (ERE) of target gene promoters; subsequent activation or repression of the target gene is mediated through 2 distinct transactivation domains (ie, AF-1 and AF-2) of the receptor. The estrogen receptor also mediates gene transcription using different response elements (ie, AP-1) and other signal pathways. Recent advances in the molecular pharmacology of estrogen and estrogen receptors have resulted in the development of selective estrogen receptor modulators (eg, clomiphene, raloxifene, tamoxifen, toremifene), agents that bind and activate the estrogen receptor but that exhibit tissue-specific effects distinct from estrogen. Tissue-specific estrogen-agonist or -antagonist activity of these drugs appears to be related to structural differences in their estrogen receptor complex (eg, specifically the surface topography of AF-2 for raloxifene) compared with the estrogen (estradiol)-estrogen receptor complex. A second estrogen receptor also has been identified, and existence of at least 2 estrogen receptors (ER-alpha, ER-beta) may contribute to the tissue-specific activity of selective modulators. While the role of the estrogen receptor in bone, cardiovascular tissue, and the CNS continues to be studied, emerging evidence indicates that the mechanism of action of estrogen receptors in these tissues differs from the manner in which estrogen receptors function in reproductive tissue. /Estrogen General Statement/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130
Intracellular cytosol-binding proteins for estrogens have been identified in estrogen-responsive tissues including the female genital organs, breasts, pituitary, and hypothalamus. The estrogen-binding protein complex (ie, cytosol-binding protein and estrogen) distributes into the cell nucleus where it stimulates DNA, RNA, and protein synthesis. The presence of these receptor proteins is responsible for the palliative response to estrogen therapy in women with metastatic carcinoma of the breast. /Estrogen General Statement/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130
Estrogens have generally favorable effects on blood cholesterol and phospholipid concentrations. Estrogens reduce LDL-cholesterol and increase HDL-cholesterol concentrations in a dose-related manner. The decrease in LDL-cholesterol concentrations associated with estrogen therapy appears to result from increased LDL catabolism, while the increase in triglyceride concentrations is caused by increased production of large, triglyceride-rich, very-low-density lipoproteins (VLDLs); changes in serum HDL-cholesterol concentrations appear to result principally from an increase in the cholesterol and apolipoprotein A-1 content of HDL2- and a slight increase in HDL3-cholesterol. /Estrogen General Statement/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130
For more Mechanism of Action (Complete) data for ESTRADIOL (7 total), please visit the HSDB record page.

9.9 Human Metabolite Information

9.9.1 Tissue Locations

  • Adipose Tissue
  • Adrenal Cortex
  • Adrenal Gland
  • Brain
  • Epidermis
  • Fibroblasts
  • Kidney
  • Liver
  • Neuron
  • Ovary
  • Placenta
  • Platelet
  • Prostate
  • Skeletal Muscle
  • Spleen
  • Testis

9.9.2 Cellular Locations

  • Cytoplasm
  • Endoplasmic reticulum
  • Extracellular
  • Membrane

9.9.3 Metabolite Pathways

9.10 Biochemical Reactions

9.11 Transformations

10 Use and Manufacturing

10.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
MEDICATION

Use (kg; approx.) in Germany (2009): >250

Use (kg) in USA (2002): 515

Consumption (g per capita; approx.) in Germany (2009): 0.00305

Consumption (g per capita) in the USA (2002): 0.00183

Calculated removal (%): 67

For the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).

10.1.1 Use Classification

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
Veterinary Drug -> PRODUCTION_AID; -> JECFA Functional Classes
Pharmaceuticals -> Animal Drugs -> Approved in Taiwan
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

10.1.2 Household Products

California Safe Cosmetics Program (CSCP)

Cosmetics product ingredient: Estradiol 17beta (Estradiol)

Also known as: estradiol; oestradiol; E2; estrace

Source: Estradiol is a form of estrogen, a steroid hormone that is critical to the function of the reproductive system. Estradiol in cosmetics often comes from placental extract. Estradiol may also be isolated from urine of pregnant horses or synthesized from a plant-based compound. Placental extracts containing estradiol are added to some skin and hair treatments, including shampoos.

Potential health impacts: The major routes of exposure to estradiol in cosmetics are by absorption through the skin or by ingestion, depending on the specific product. Exposure to certain estrogens during fetal development is known to cause abnormalities of the urinary system or genital organs in both females and males. The U.S. Food and Drug Administration (U.S. FDA) categorizes estradiol as Pregnancy Category X, meaning that there is a risk to human fetuses from exposure to it. Studies of women exposed to estradiol have found an increase in risk of endometrial cancer. Use of estrogens after menopause is associated with an increased risk of breast cancer, as well as stroke, blood clots, and heart attacks. The National Toxicology Program (NTP) classifies estradiol and other steroidal estrogens as known human carcinogens.

Product count: 2

10.2 Methods of Manufacturing

Estradiol-17beta is produced commercially by the reduction of estrone using, for example, complex metal hydrides, such as sodium borohydride and lithium aluminum hydride.
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. V21 287 (1979)
Has been isolated from ovarian follicular fluid and from placental tissue ... It is usually prepared through reduction of the 17-keto group of Estrone.
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1463
Isolated from human and mare pregnancy urine.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512
Commercial synthesis from cholesterol or ergosterol.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512
Has also been isolated from urine of pregnant women and mares.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 635

10.3 Impurities

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. V91 385 (2007)

10.4 Formulations / Preparations

Estradiol is available commercially as oral and vaginal tablets, as a metered topical gel, as topical transdermal patches, as a vaginal cream and as an extended-release vaginal insert (ring).
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. V91 384 (2007)
Grade: NF (beta-form)
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512
Commonly used preparations are the benzoate, dipropionate, and valerate, as well as ethinylestradiol.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512

10.5 General Manufacturing Information

Carcinogen
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512

11 Identification

11.1 Analytic Laboratory Methods

Method: AOAC 971.43; Procedure: colorimetric method; Analyte: beta-estradiol; Matrix: drugs; Detection Limit: not provided.
Official Methods of Analysis of AOAC International, 18th Edition Online. beta-Estradiol (50-28-2). Available from, as of March 22, 2011: https://www.aoac.org
Method: AOAC 973.76; Procedure: spectrofluorometric method; Analyte: estradiol valerate; Matrix: drugs; Detection Limit: not provided. /Estradiol valerate/
Official Methods of Analysis of AOAC International, 18th Edition Online. Estradiol Valerate (979-32-8). Available from, as of March 22, 2011: https://www.aoac.org
Analyte: estradiol; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 32/The National Formulary, NF 27; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2300-4 (2009)
Analyte: estradiol; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 32/The National Formulary, NF 27; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2300-4 (2009)
For more Analytic Laboratory Methods (Complete) data for ESTRADIOL (13 total), please visit the HSDB record page.

11.2 Clinical Laboratory Methods

An estradiol test system is a device intended to measure estradiol, an estrogenic steroid, in plasma. Estradiol measurements are used in the diagnosis and treatment of various hormonal sexual disorders and in assessing placental function in complicated pregnancy.
21 CFR 862.1260 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 16, 2011: https://www.ecfr.gov
As estrogens (total, in pregnancy) test system is a device intended to measure total estrogens in plasma, serum, and urine during pregnancy. The device primarily measures estrone plus estradiol. Measurements of total estrogens are used to aid in the diagnosis and treatment of fetoplacental distress in certain cases of high-risk pregnancy.
21 CFR 862.1270 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 15, 2011: https://www.ecfr.gov
As estrogens (total, nonpregnancy) test system is a device intended to measure the level of estrogens (total estrone, estradiol, and estriol) in plasma, serum, and urine of males and nonpregnant females. Measurement of estrogens (total, nonpregnancy) is used in the diagnosis and treatment of numerous disorders, including infertility, amenorrhea (absence of menses) differentiation of primary and secondary ovarian malfunction, estrogen secreting testicular and ovarian tumors, and precocious puberty in females.
21 CFR 862.1275 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 15, 2011: https://www.ecfr.gov
Analytical methods for estradiol-17beta:
Sample Matrix
Animal tissue
Sample Preparation
Homogenize (aqueous acetonitrile); hydrolyze (hydrochloric acid); perform a series of extractions and washings.
Assay Procedure
High-performance TLC: UV-densitometry (287 nm)
Sensitivity or Limit of Detection
10 nanogram
Sample Matrix
Plasma
Sample Preparation
Extract (diethyl ether); evaporate; column chromatography; evaporate; dissolve (ethanol); add enzyme reagent and incubate; add base and neutralize; add cycling reagent and incubate; add 6-phosphogluconate reagent and incubate.
Assay Procedure
Fluorimetry
Sensitivity or Limit of Detection
~ 7 picogram
Sample Matrix
Plasma
Sample Preparation
Add radioactive steroids; hydrolyze (hydrochloric acid); perform a series of estractions and washings; TLC; elute; add Ittrich reagent
Assay Procedure
Fluorimetry
Sensitivity or Limit of Detection
8 nanogram
Sample Matrix
Plasma
Sample Preparation
Extract Idiethyl ether); column chromatography (Sephadex LH-20); add immobilized antibody; incubate; add estradiol-horse radish peroxidase conjugate, incubate, centrifuge and add fluorogenic substrate.
Assay Procedure
Enzyme immunoassay, fluorimetry (420 nm)
Sensitivity or Limit of Detection
~ 50 picogram
Sample Matrix
Serum
Sample Preparation
Extract
Assay Procedure
High-performance TLC; UV-densitometry ((287 nm)
Sensitivity or Limit of Detection
20 nanogram
Sample Matrix
Serum
Sample Preparation
Add tetradeuteriated estradiol-17beta internal standard; extract (diethyl ether); column chromatography (Sephadex LH-20) and derivatize (trimethylsilyl)
Assay Procedure
GC/MS
Sensitivity or Limit of Detection
~ 10 picogram
Sample Matrix
Serum
Sample Preparation
Add tracer solution, incubate and extract (diethyl ether); evaporate, dissolve (buffer), add antiserum and incubate; add dextran-coated charcoal and centrifuge.
Assay Procedure
Radioimmunoassay
Sensitivity or Limit of Detection
5-10 picogram
Sample Matrix
Serum and urine
Sample Preparation
Extract (diethyl ether) and derivatize (trimethylsilyl)
Assay Procedure
GC/MS
Sensitivity or Limit of Detection
2 picogram
Sample Matrix
Urine
Sample Preparation
Hydrolyze (enzyme); extract (ethyl acetate, hexane, ethanol); column chromatography (ion exchange) and derivatize (trimethylsilyl)
Assay Procedure
Gas chromatography/flame-ionization detection
Sensitivity or Limit of Detection
~ 40 ug/L (50 mL sample)
Sample Matrix
Urine
Sample Preparation
Extract
Assay Procedure
High-performance TLC; UV-densitometry (287 nm)
Sensitivity or Limit of Detection
10 nanogram
Sample Matrix
Urine (as the glucosiduronate)
Sample Preparation
Add phosphate buffered saline, antiserum, tracer solution and incubate; add dextran-coated charcoal, incubate and centrifuge
Assay Procedure
Radioimmunoassay
Sensitivity or Limit of Detection
~ 6 picogram
Sample Matrix
Ovarian tissue
Sample Preparation
Dissect, dry and homogenize
Assay Procedure
Mass spectrometry
Sensitivity or Limit of Detection
~ 1 nanogram
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. V21 292 (1999)

11.3 NIOSH Analytical Methods

12 Safety and Hazards

12.1 Hazards Identification

12.1.1 GHS Classification

Pictogram(s)
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H350 (39.6%): May cause cancer [Danger Carcinogenicity]

H351 (57.9%): Suspected of causing cancer [Warning Carcinogenicity]

H360 (82.4%): May damage fertility or the unborn child [Danger Reproductive toxicity]

H360FD (11.3%): May damage fertility; May damage the unborn child [Danger Reproductive toxicity]

H362 (32.1%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]

H372 (34.6%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

H400 (30.2%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]

H410 (35.8%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P260, P263, P264, P270, P273, P280, P318, P319, P391, 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 159 reports by companies from 19 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.

12.1.2 Hazard Classes and Categories

Carc. 1A (39.6%)

Carc. 2 (57.9%)

Repr. 1A (82.4%)

Repr. 1A (11.3%)

Lact. (32.1%)

STOT RE 1 (34.6%)

Aquatic Acute 1 (30.2%)

Aquatic Chronic 1 (35.8%)

12.2 Accidental Release Measures

12.2.1 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

12.3 Handling and Storage

12.3.1 Storage Conditions

Do not store unpouched. Apply immediately upon removal from the protective pouch.
US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806
Store at controlled room temperature 15 to 30 °C (59 to 86 °F).
US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686

12.4 Exposure Control and Personal Protection

12.4.1 Allowable Tolerances

No residues of estradiol, resulting from the use of estradiol or any of the related esters, are permitted in excess of the following increments above the concentrations of estradiol naturally present in untreated animals: (a) In uncooked edible tissues of heifers, steers, and calves: (1) 120 parts per trillion for muscle. (2) 480 parts per trillion for fat. (3) 360 parts per trillion for kidney. (4) 240 parts per trillion for liver. (b) In uncooked edible tissues of lambs: (1) 120 parts per trillion for muscle. (2) 600 parts per trillion for fat, kidney, and liver.
21 CFR 556.240 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 16, 2011: https://www.ecfr.gov

12.5 Stability and Reactivity

12.5.1 Hazardous Reactivities and Incompatibilities

A carcinogen.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 512

12.6 Regulatory Information

California Safe Cosmetics Program (CSCP) Reportable Ingredient

Hazard Traits - Carcinogenicity

Authoritative List - Prop 65

Report - regardless of intended function of ingredient in the product

REACH Registered Substance
New Zealand EPA Inventory of Chemical Status
Oestradiol: Does not have an individual approval but may be used under an appropriate group standard

12.6.1 FDA Requirements

Estradiol. For implantation in steers and heifers as follows: ... For increased rate of weight gain in suckling and pastured growing steers; for improved feed efficiency and increased rate of weight gain in confined steers and heifers.
21 CFR 522.840 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 16, 2011: https://www.ecfr.gov
Estradiol valerate and norgestomet in combination. ... For synchronization of estrus/ovulation in cycling beef cattle and non-lactating dairy heifers. /Estradiol valerate and norgestomet in combination/
21 CFR 522.850 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 16, 2011: https://www.ecfr.gov
Estradiol benzoate and testosterone propionate. ... For implantation in heifers as follows: ... For increased rate of weight gain and improved feed efficiency. /Estradiol benzoate and testosterone propionate/
21 CFR 522.842 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 16, 2011: https://www.ecfr.gov
Progesterone and estradiol benzoate. Conditions of use in cattle. It is used for implantation as follows: (1) Suckling beef calves ... For increased rate of weight gain ... (2) Steers ... For increased rate of weight gain and improved feed efficiency ... (3) Steers fed in confinement for slaughter ... For additional improvement in rate of weight gain. /Progesterone and estradiol benzoate/
21 CFR 522.1940 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 16, 2011: https://www.ecfr.gov
For more FDA Requirements (Complete) data for ESTRADIOL (13 total), please visit the HSDB record page.

12.7 Other Safety Information

Chemical Assessment

IMAP assessments - Estra-1,3,5(10)-triene-3,17-diol, (17.beta.)-: Environment tier I assessment

IMAP assessments - Estra-1,3,5(10)-triene-3,17-diol, (17.beta.)-: Human health tier I assessment

13 Toxicity

13.1 Toxicological Information

13.1.1 Toxicity Summary

Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.

13.1.2 RAIS Toxicity Values

Inhalation Unit Risk (IUR) (ug/m^3)^-1
0.011
Inhalation Unit Risk Reference
CALEPA
Oral Slope Factor (CSFo)(mg/kg-day)^-1
39
Oral Slope Factor Reference
CALEPA

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

Chemical
17-beta-Estradiol
Chemical Classes
Hormone and(or) waste-water effluent contaminant
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

13.1.4 Drug Induced Liver Injury

Compound
estradiol
DILI Annotation
Less-DILI-Concern
Severity Grade
2
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

13.1.5 Evidence for Carcinogenicity

Evaluation: There is sufficient evidence in humans for the carcinogenicity of post-menopausal estrogen therapy. There is sufficient evidence in experimental animals for the carcinogenicity of estradiol and estrone. There is limited evidence in experimental animals for the carcinogenicity of conjugated equine estrogens, equilin and estriol. There is inadequate evidence in experimental animals for the carcinogenicity of d-equilenin. Overall evaluation: Post-menopausal estrogen therapy is carcinogenic to humans (Group 1). /Post-menopausal estrogen therapy/
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. V72 503 (1999)

13.1.6 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

13.1.7 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited information on the use of estradiol during breastfeeding indicates that the route of administration and dosage form have influences on the amount transferred into breastmilk. Vaginal administration results in measurable amounts in milk, but transdermal patches do not. Maternal doses of up to 200 mcg daily transdermally do not increase estradiol or estriol in breastfed infants or cause any adverse effects in breastfed infants. Vaginal administration results in unpredictable peak times for estradiol in breastmilk, so timing of the dose with respect to breastfeeding is probably not useful. Milk estradiol levels have not been studied after use of the estradiol gel, but maternal blood levels only increase slightly in a dose-dependent manner.

Estrogens can decrease the milk supply, especially if started before the milk supply is well established at about 6 weeks postpartum. The decrease can happen over the first few days of estrogen exposure. A case report of inadequate milk production and inadequate infant weight gain was possibly caused by transdermal estradiol initiated on the first day postpartum, but 2 small studies found no such effect when the drug was initiated after lactation was well established.

◉ Effects in Breastfed Infants

A mother who had severe postpartum depression with 2 previous infants was prescribed a transdermal estradiol patch that released 50 mcg daily beginning on day 1 postpartum to prevent recurrence of depression. At 11 days of age, the infant was jaundiced and had gained only 60 grams since birth. With more frequent nursing, weight gain improved, but remained inadequate until day 28 when the estradiol was discontinued. The infant then experienced above average weight gain through day 66 postpartum. The delayed and reduced weight gain was possibly caused by estradiol.

Six nursing mothers received transdermal estradiol as part of a study comparing estradiol to sertraline and placebo for postpartum depression. The mothers received estradiol dosages between 50 and 200 mcg daily (mean 133 mcg daily) at the time of serum level analysis at 4 and 8 weeks of therapy. Four of the 6 infants were exclusively breastfed and the other two were more than 50% breastfed. There was no difference in infant length, weight, and head circumference nor in the average daily gains in any of these parameters between treatments.

◉ Effects on Lactation and Breastmilk

Thirteen women who were 12 weeks postpartum and fully breastfeeding their infants were given a transdermal patch that released 100 mcg of estradiol daily. The average number of breast feeds per day did not change significantly during 3 days of patch application.

Nineteen women who were 6 weeks postpartum, using a barrier contraceptive method and breastfeeding their infants were randomized to transdermal patches that released estradiol 50 mcg daily or placebo patches for 12 weeks. An additional control group received no patches. The number of breast feeds per day decreased in all groups over the course of the study, but there were no important differences among the groups.

A retrospective cohort study compared 371 women who received high-dose estrogen (either 3 mg of diethylstilbestrol or 150 mcg of ethinyl estradiol daily) during adolescence for adult height reduction to 409 women who did not receive estrogen. No difference in breastfeeding duration was found between the two groups, indicating that high-dose estrogen during adolescence has no effect on later breastfeeding.

A transgender woman took and spironolactone 50 mg twice daily to suppress testosterone, domperidone 10 mg three times daily, increasing to 20 mg four times daily, oral micronized progesterone 200 mg daily and oral estradiol to 8 mg daily and pumped her breasts 6 times daily to induce lactation. After 3 months of treatment, estradiol regimen was changed to a 0.025 mg daily patch and the progesterone dose was lowered to 100 mg daily. Two weeks later, she began exclusively breastfeeding the newborn of her partner. Breastfeeding was exclusive for 6 weeks, during which the infant's growth, development and bowel habits were normal. The patient continued to partially breastfeed the infant for at least 6 months.

A transgender woman was taking sublingual estradiol 4 mg twice daily, spironolactone 100 mg twice daily and progesterone 200 mg at bedtime for gender-affirming therapy. In order to prepare for the birth of the infant being carried by her partner, sublingual estradiol was increased to 6 mg twice daily and progesterone was increased to 400 mg at bedtime. Domperidone 10 mg twice daily was also started to increase serum prolactin levels and later increased to 20 mg 4 times daily. Before the delivery date, progesterone was stopped, spironolactone was decreased to 100 mg daily and estradiol was changed to 25 mcg per day transdermally. At day 59 postpartum, estradiol was changed to 2 mg per day sublingually and spironolactone was increased to 100 mg twice daily. The patient was able to produce up to 240 mL of milk daily. The patient was able to produce up to 240 mL of milk daily containing typical macronutrient and oligosaccharide levels.

A transgender woman who wished to breastfeed was given estradiol transdermal patch 150 mcg daily and progesterone 100 mg daily by mouth. Later estradiol spray 100 mcg and domperidone 10 mg 4 times daily were added. Domperidone dosage was then doubled to 20 mg 4 times daily and progesterone was doubled to 100 mg twice daily. After further adjustment of estradiol and progesterone dosages, 7 mL of milk was produced with pumping, but 2 weeks after the infant’s birth, lactation induction was discontinued at the patient’s request.

A 50-year-old transgender woman wished to breastfeed her grandchild was taking baseline treatment with estradiol 0.3 mg transdermal patch every 72 hours and micronized progesterone 200 mg oral once daily. To initiate lactation, her estradiol dose was increased to a 0.4 mg transdermal patch every 72 hours and nipple stimulation was initiated. Later the patient’s progesterone was increased to 300 mg daily and metoclopramide oral 10 mg three times daily was initiated. She lactated for a total of two weeks and nursed the four-month-old infant on multiple occasions. Her peak milk production was 30 mL from her larger right breast, and 8 mL from her smaller left breast.

A 50-year-old transgender woman wished to breastfeed the expected infant of her partner. She was given estradiol in dosages increasing from 6 to 8 mg (6 mg oral and 2 mg gel) daily along with progesterone and domperidone to stimulate lactation. Progesterone was discontinued after 123 days of treatment. The patient was able to produce small quantities of milk and was able to directly breastfeed the infant.

13.1.8 Symptoms

Can cause nausea and vomiting, and withdrawal bleeding may occur in females.

13.1.9 Acute Effects

13.1.10 Interactions

Estrogens may interfere with the effects of bromocriptine; dosage adjustment may be necessary. /Estrogens/
USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc., p. 1385
A combination of testosterone and estradiol-B17 after treatment with methylnitrosurea also resulted in the development of adenocarciomas of the prostate.
Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995., p. 209
Concurrent use with estrogens may increase calcium absorption and exacerbate nephrolithiasis in susceptible individuals; this can be used to therapeutic advantage to increase bone mass. /Estrogens/
USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc., p. 1385
Concurrent use /of glucocorticoid corticosteroids/ with estrogens may alter the metabolism and protein binding of the glucocorticoids, leading to decreased clearance, increased elimination half-life, and increased therapeutic and toxic effects of the glucocorticoids; glucocorticoid dosage adjustment may be required during and following concurrent use. /Estrogens/
USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc., p. 1385
For more Interactions (Complete) data for ESTRADIOL (11 total), please visit the HSDB record page.

13.1.11 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

13.1.12 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. Treatment of overdose consists of discontinuation of estradiol together with institution of appropriate symptomatic care.
US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686
/SIGNS AND SYMPTOMS/ Estradiol implant overdose (200 mg estradiol by implant every 3 weeks) led to fluid retention, facial swelling, and pitting edema of the thighs. Serum estradiol levels were elevated and fell over several years after the implants were discontinued. In two other patients, repeated implants of estradiol over a 1- to 2-year period led to hypertension, flushing, fatigue, and nasal congestion. Serum estradiol concentrations of 200 to 300 nmol/L or lower should guide timing for other implants.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 740
/CASE REPORTS/ A 61-year-old woman with a persistent hand and foot dermatitis developed multiple contact allergies to topical steroids. She had a past history of allergic contact dermatitis (ACD) to a hormone replacement patch containing both estrogen and progesterone. The aim of this report is to highlight the potential cross-reactions between topical corticosteroids and sex steroids. Patch testing with a standard series, a corticosteroid series, and the sex steroids progesterone and estradiol was performed. Positive ACD reactions to hydroxyprogesterone, progesterone, and estradiol occurred. There were also multiple corticosteroid allergies. This case demonstrates that patients who develop contact allergies to sex steroids are at risk of developing multiple corticosteroid allergies.
Lamb SR, Wilkinson SM; Dermatitis 15 (2): 78-81 (2004)
/CASE REPORTS/ ... A 47-year-old, postmenopausal woman developed eczematous lesions at the sites of application of a estradiol therapeutic transdermal system and successively at the sites of application of a gel containing estradiol. Due to the topical intolerance, the therapy was switched to oral estrogen, which caused a systemic pruritic rash. Positive patch tests with estradiol led to the diagnosis of type IV allergic dermatitis due to transdermal estradiol and to a gel containing estradiol. Systemic contact dermatitis due to oral estradiol was also diagnosed. ...
Corazza M et al; J Reprod Med 47 (6): 507-9 (2002)
For more Human Toxicity Excerpts (Complete) data for ESTRADIOL (29 total), please visit the HSDB record page.

13.1.13 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Administration of 0.5 mg/L estradiol-17beta in the drinking water for 19 months to C3H/HeJ (MTV+) female mice resulted in a significantly increased mammary tumor incidence (27/99, compared with 11/100 in controls); a combination of estradiol-17beta with a prolactin inhibitor, 2-bromo-a-ergocryptine (CB-154), prevented this increased tumor incidence (9/100).
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. V21 298 (1979)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 48 C3H HeJ (MTV + ) mice were fed 0, 100, 1000 and 5000 ug/kg of diet estradiol-17beta for 24 months starting at 6 weeks of age. Mammary adenocarcinomas were found in 4/47, 0/35, 6/36 and 8/48 animals in the respective groups after 52 weeks. Other malignant tumors occurred in those given 100 ug/kg: 1 adenocarcinoma of the cervix and 1 osteosarcoma of the cranium; in the 5000 ug/kg group, 2 adenocarcinomas of the uterus, 3 adenocarcinomas of the cervix and 1 adenoacanthoma of the uterus were seen. No such tumors were described in the controls.
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. V21 298 (1979)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Twice-weekly sc or im injections of 80 pg estradiol-17beta for 6 months (total dose, 3.3-4.2 mg) did not increase the incidence of mammary tumors in groups of 40 intact and 40 ovariectomized female Marsh Buffalo mice [MTV+] above that found in untreated controls. However, lymphosarcomas occurred earlier (between 3 and 10 months) and in a higher incidence (28% in intact, 47% in ovariectomized) than in controls (10%), the first tumor appearing at 12 months. With discontinuous treatment in groups of 36-43 intact and castrated males of the same strain, lymphoid tumors occurred in 34% of castrates, compared with 8% in intact treated males and 5% in controls; the tumors developed much earlier in castrates (at 6-14 months) than in the other groups.
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. V21 299 (1979)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In an unspecified number of female mice of reciprocal crosses between C57 and CBA strains injected subcutaneously with weekly doses of 16.6 or 50 ug estradiol 3-benzoate (vehicle not stated) commencing at 4-8 weeks of age, cervical lesions, ranging from invasion to gross tumors which invaded adjacent tissues, were seen in 15/24 mice with C57 mothers and in 10/20 with CBA mothers and surviving for more than 52 weeks. In the latter group there was a high incidence of mammary cancer, which reduced the lifespan. No lesions were seen before 59 weeks in either group. Of 10 mice in the two groups which survived more than 86 weeks, 6 had lesions at death. Although none of the tumors metastasized, it was concluded that the range of lesions seen probably represented various stages of carcinoma development. No cervical tumors occurred among an equal number of control mice. /Estradiol 3-benzoate/
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. V21 300 (1979)
For more Non-Human Toxicity Excerpts (Complete) data for ESTRADIOL (23 total), please visit the HSDB record page.

13.1.14 Populations at Special Risk

Estrogens have been reported to produce keratoconus (steepening of corneal curvature) and intolerance to contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen therapy should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered. Although neuro-ocular lesions such as optic neuritis or retinal thrombosis have been associated with use of estrogen-containing oral contraceptives, these lesions have not been reported to date with estrogens. If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions occur during therapy with an estrogen, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted. /Estrogen General Statement/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127
Endocrine function test results (eg, glucose tolerance, thyroid function) may be altered in patients receiving large dosages of estrogens. Decreased glucose tolerance has occurred in women receiving estrogen-containing oral contraceptives and may occur in patients receiving large dosages of estrogens. Prediabetic and diabetic patients should be carefully monitored during estrogen therapy. /Estrogen General Statement/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126
In patients with hypertriglyceridemia, estrogen therapy may be associated with further increases in plasma triglycerides resulting in pancreatitis and other complications. If acute pancreatitis occurs, estrogens should be discontinued. The risk of gallbladder disease appears to be increased 2- to 4-fold in postmenopausal women receiving estrogen replacement therapy. In one study, an increased risk of gallbladder disease occurred after 2 years of use of the drugs and doubled after 4 or 5 years of use. In another study, an increased risk of gallbladder disease was apparent between 6-12 months of use. /Estrogen General Statement/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126
Data from studies on tobacco smoking and the use of high-dose estrogen oral contraceptives indicate that there is an increased risk of serious cardiovascular side effects, including cerebrovascular accident, transient ischemic attacks, thrombophlebitis, and pulmonary embolism; risk increases with increasing tobacco usage and with age, especially in women over 35 years of age; it is not known whether any elevation of risk occurs with tobacco smoking during the use of ovarian hormone therapy. Metabolism of estrogens may also be increased by smoking, resulting in a decreased estrogenic effect. /Estrogens/
USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc., p. 1385

13.1.15 Protein Binding

More than 95% of estrogens are found to circulate in the blood bound to sex hormone binding globulin (SHBG) and albumin.

13.2 Ecological Information

13.2.1 Ecotoxicity Values

EC50; Species: Daphnia magna (Water flea, age <24 hr neonate newly released); Conditions: freshwater, static, 20 °C; Concentration: 1550 ug/L for 24 hr (95% confidence interval: 1050-2040 ug/L); Effect: development, decreased molting /100% purity, 17beta-estradiol/
Brennan SJ et al; Chemosphere 64: 49-55 (2006) as cited in the ECOTOX database.
EC50; Species: Daphnia magna (Water flea, age <24 hr neonate newly released); Conditions: freshwater, static, 20 °C; Concentration: 2040 ug/L for 48 hr (95% confidence interval: 1720-2360 ug/L); Effect: development, decreased molting /100% purity, 17beta-estradiol/
Brennan SJ et al; Chemosphere 64: 49-55 (2006) as cited in the ECOTOX database.
EC50; Species: Daphnia magna (Water flea, age <24 hr neonate newly released); Conditions: freshwater, static, 20 °C; Concentration: 3670 ug/L for 24 hr (95% confidence interval: 3460-3880 ug/L); Effect: intoxication, immobilization /100% purity, 17beta-estradiol/
Brennan SJ et al; Chemosphere 64: 49-55 (2006) as cited in the ECOTOX database.
EC50; Species: Daphnia magna (Water flea, age <24 hr neonate newly released); Conditions: freshwater, static, 20 °C; Concentration: 2870 ug/L for 48 hr (95% confidence interval: 2670-3070 ug/L); Effect: intoxication, immobilization /100% purity, 17beta-estradiol/
Brennan SJ et al; Chemosphere 64: 49-55 (2006) as cited in the ECOTOX database.
For more Ecotoxicity Values (Complete) data for ESTRADIOL (14 total), please visit the HSDB record page.

13.2.2 Environmental Fate / Exposure Summary

Estradiol's production and use as an estrogen may result in its release to the environment through various waste streams. Estradiol is a natural steroidal estrogen hormone released by mammals. If released to air, an estimated vapor pressure of 6.4X10-9 mm Hg at 25 °C indicates estradiol will exist solely in the particulate phase in the atmosphere. Particulate-phase estradiol will be removed from the atmosphere by wet or dry deposition. Estradiol irradiated with a xenon arc lamp exhibited a photodegradation half-life of 2 hours in river water and 41.7 hours in air-saturated purified water, and therefore estradiol may be susceptible to direct photolysis by sunlight. If released to soil, estradiol is expected to have no mobility based upon an estimated Koc of 30,000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 3.6X10-11 atm-cu m/mole. A 6% mineralized of estradiol in 5 days after application to a agricultural soil microcosm suggests biodegradation is not an important environmental fate process. If released into water, estradiol is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 200 suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism. 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 estradiol may occur through inhalation and dermal contact with this compound at workplaces where estradiol is produced or used. Exposure to estradiol via ingestion will occur when administered drugs containing this compound. Monitoring data indicate that the general population may be exposed to estradiol at well below the therapeutic dose via ingestion of drinking water and dermal contact with contaminated sediments. (SRC)

13.2.3 Natural Pollution Sources

Estradiol is a natural steroidal estrogen hormone released by mammals(1). 17beta-Estradiol is the natural female steroid hormone with the greatest estrogenic activity(2).
(1) Khanal SK et al; Environ Sci Technol 40: 6537-6546 (2006)
(2) Geyer HJ et al; Bioaccumulation and occurrence of endocrine-disrupting chemicals (EDCs), persistent organic pollutants (POPs), and other organic compounds in fish and other organisms including humans. In: Handb. Environ. Chem., Vol. 2, pt. J, Beek B, ed., Berlin, Germany: Spring-Verlag pp. 1-166 (2002)

13.2.4 Artificial Pollution Sources

Estradiol's production and use as an estrogen(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. Whitehouse Station, NJ: Merck and Co., Inc., p. 635 (2006)

13.2.5 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 30,000 indicates that estradiol is expected to be immobile in soil(SRC). Volatilization of estradiol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.6X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Estradiol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.4X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). A 6% mineralized of estradiol in 5 days after application to a agricultural soil microcosm(5) suggests biodegradation is not an important environmental fate process in soil(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Fan Z et al; Chemosphere 67: 886-895 (2007)
(3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(5) Fan Z et al; Chemosphere 67: 886-895 (2007)
AQUATIC FATE: Based on a classification scheme(1), a Koc value of 30,000(2) indicates that estradiol 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 3.6X1011 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 200(SRC), from its log Kow of 4.01(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). A 6% mineralized of estradiol in 5 days after application to a agricultural soil microcosm(8) suggests biodegradation is not an important environmental fate process in water(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Fan Z et al; Chemosphere 67: 886-895 (2007)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Franke C et al; Chemosphere 29: 1501-14 (1994)
(6) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 158 (1995)
(7) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available from, as of Feb 7, 2011: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(8) Fan Z et al; Chemosphere 67: 886-895 (2007)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), estradiol, which has an estimated vapor pressure of 6.4X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase estradiol may be removed from the air by wet or dry deposition(SRC). Estradiol irradiated with a xenon arc lamp exhibited a photodegradation half-life of 2 hours in river water and 41.7 hours in air-saturated purified water(3), and therefore estradiol may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; 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) Lin AY-C, Reinhard M; Environ Toxicol Chem 24: 1303-1309 (2005)

13.2.6 Environmental Biodegradation

AEROBIC: 4-14C-Labeled estradiol, present at 1.5 mg/L, was 6% mineralized in 5 days after application to a microcosm employing 210 g of agricultural soil(Hamar soil: 2.23% organic mater, 14.0% clay, 19.0% silt, 67% sand) in 250 mL flasks(1). 17beta-Estradiol is 85-90% removed by conventional wastewater treatment, occurring mainly through sorption to sludge followed by biodegradation. Conjugated estrogens are hydrolyzed into free estrogens and glucuronide/sulfuric acid in the presence of Eschericia coli(2). Mineralization of estrogens may be enhanced by up to 147% or depressed up to 50%, depending on soil and organic waste(3).
(1) Fan Z et al; Chemosphere 67: 886-895 (2007)
(2) Khanal SK et al; Environ Sci Technol 40: 6537-6546 (2006)
(3) Stumpe B, Marschner B; J Environ Biol 39: 907-916 (2010)
AEROBIC: Organic waste effects on mineralization of 17beta-estradiol in agricultural soils(1).
Soil
Sand
Organic Waste (%)
Control
Soil Organic Content
0.0
% 14CO2 evolution of added 14C
0.2
Organic Waste (%)
Liquid cattle manure
Soil Organic Content
1.8
% 14CO2 evolution of added 14C
36.9
Organic Waste (%)
Solid swine manure
Soil Organic Content
1.9
% 14CO2 evolution of added 14C
38.9
Organic Waste (%)
Biosolid
Soil Organic Content
1.1
% 14CO2 evolution of added 14C
51.9
Soil
Koeln (pH 7.4; SOC 0.7%; clay 18%; dissolved organic carbon 7 mg/L))
Organic Waste (%)
Control
Soil Organic Content
0.7
% 14CO2 evolution of added 14C
4.8
Organic Waste (%)
Liquid cattle manure
Soil Organic Content
2.5
% 14CO2 evolution of added 14C
14.9
Organic Waste (%)
Solid swine manure
Soil Organic Content
2.5
% 14CO2 evolution of added 14C
11.5
Organic Waste (%)
Biosolid
Soil Organic Content
1.8
% 14CO2 evolution of added 14C
45.8
(1) Stumpe B, Marschner B; J Environ Biol 39: 907-916 (2010)
ANAEROBIC: The fate of 17beta-estradiol in groundwater contaminated by wastewater treatment plant effluent was simulated using oxic laboratory microcosms containing sediments from the USGS Cape Cod Toxic Substances Hydrology research site. This aquifer has been subjected to 60 years of continuous rapid infiltration disposal of wastewater treatment plant effluent. Using uniform ring-labeled 14CO2 estradiol at a concentration of 34 ug/L, 20-90% was recovered as 14CO2 after 54 days incubation in the dark at 23 °C(1). 4-14C-labeled estradiol, present at 1.5 mg/L, was not mineralized in 5 days after application to a microcosm employing 210 g of agricultural soil(Hamar soil: 2.23% organic mater, 14.0% clay, 19.0% silt, 67% sand) in 250 mL flasks(1).
(1) Barber LB et al; Environ Sci Technol 43: 4843- 50 (2009)
(2) Fan Z et al; Chemosphere 67: 886-895 (2007)

13.2.7 Environmental Abiotic Degradation

Estradiol is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Estradiol irradiated with a xenon arc lamp exhibited a photodegradation half-life of 2 hours in river water and 41.7 hours in air-saturated purified water(2). Photodegradation of 17 beta-estradiol in dilute aqueous solution irradiated at >290 nm resulted in the formation of various quinone derivatives(3).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)
(2) Lin AY-C, Reinhard M; Environ Toxicol Chem 24: 1303-1309 (2005)
(3) Mazellier P et al; Chemosphere 73: 1216-1223 (2008)

13.2.8 Environmental Bioconcentration

An estimated BCF of 200 was calculated in fish for estradiol(SRC), using a log Kow of 4.01(1) and a regression-derived equation(2). An estimated log BCF of 2.65 was calculated in fish for estradiol using a food-web model(3), corresponding to a BCF of 450(SRC). According to a classification scheme(4), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 158 (1995)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available from, as of Feb 7, 2011: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lai KM et al; Sci Total Environ 289: 159-68 (2000)
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)

13.2.9 Soil Adsorption / Mobility

Using a Drummer soil from Indiana (pH 7.1, 2.91% organic carbon, 21% clay, 13% sand, 66% silt), a log Koc of 3.45 (Freundlich constant Kd 83.2) was measured(1), corresponding to a Koc of 3,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that estradiol is expected to be immobile in soil. Kd values of 476 have been reported for estradiol in activated sludge wastewater treatment systems; it was estimated that as much as 66% of estradiol is absorbed to sludge and 0.24% sorbed to suspended particles during waste water treatment(3). Estradiol sorption was shown to increase with the amount of incorporated organic waste. In soils with an extensive history of organic waste treatments, soil organic carbon content is the controlling factor for estrogen sorption(4).
(1) Lee LS et al; Environ Sci Technol 37: 4098-4105 (2003)
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Andersen HR et al; Chemosphere 61: 139-146 (2005)
(4) Stumpe B, Marschner B; J Environ Biol 39: 907-916. (2010)
Organic waste effects on the adsorption of 17beta-estradiol in agricultural soils(1).
Soil
Sand
Organic Waste (%)
Control
Soil Organic Content
0.0
Kd (mL/g)
0.0
Koc (mL/g)
not determined
Organic Waste (%)
Liquid cattle manure
Soil Organic Content
1.8
Kd (mL/g)
25.6
Koc (mL/g)
1432
Organic Waste (%)
Solid swine manure
Soil Organic Content
1.9
Kd (mL/g)
17.6
Koc (mL/g)
941
Organic Waste (%)
Biosolid
Soil Organic Content
1.1
Kd (mL/g)
13.2
Koc (mL/g)
1220
Soil
Koeln (pH 7.4; SOC 0.7%; clay 18%; dissolved organic carbon 7 mg/L))
Organic Waste (%)
Control
Soil Organic Content
0.7
Kd (mL/g)
21.5
Koc (mL/g)
3063
Organic Waste (%)
Liquid cattle manure
Soil Organic Content
2.5
Kd (mL/g)
40.9
Koc (mL/g)
1662
Organic Waste (%)
Solid swine manure
Soil Organic Content
2.5
Kd (mL/g)
32.4
Koc (mL/g)
1275
Organic Waste (%)
Biosolid
Soil Organic Content
1.8
Kd (mL/g)
26.6
Koc (mL/g)
1516
(1) Stumpe B, Marschner B; J Environ Biol 39: 907-916 (2010)

13.2.10 Volatilization from Water / Soil

The Henry's Law constant for estradiol is estimated as 3.6X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that estradiol is expected to be essentially nonvolatile from water and moist soil surfaces(2). Estradiol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.4X10-9 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

13.2.11 Environmental Water Concentrations

GROUNDWATER: Estradiol has been detected in unspecified groundwater samples at a concentration of approximately 5 ng/L and in mantled karst aquifers in Arkansas at a concentration range of 6-66 ng/L; contamination was associated with overlying land treatment of poultry and cattle manure waste(1). It was not detected in aquifer samples from the USGS Cape Cod Toxic Substances Hydrology research site, an aquifer that has been subjected to 60 years of continuous rapid infiltration disposal of wastewater treatment plant effluent(2).
(1) Ying GG et al; Environ Int 28: 545-551 (2002)
(2) Barber LB et al; Environ Sci Technol 43: 4843-4850 (2009)
DRINKING WATER: Estradiol was detected in 1 of 19 drinking water source samples collected from U.S. water utilities between 2006 and 2007 at a maximum concentration 17 ng/L. It was detected at below the Method Reporting Limit of 0.50 ng/L in finished and distribution water samples(1). The compound was tested for but not detected (detection limit = 0.1 ng/L) in finished drinking water samples collected from the Jefferson Parish East Bank Wastewater Treatment Plant, New Orleans, Louisiana between September and November, 2001. It was not detected in finished drinking water samples collected during the same time from the A.H. Weeks Water Treatment Plant and the ENWIN Pilot Plant in Windsor, Ontario, Canada(2). 17-beta-Estradiol was detected in 5 of 10 drinking water samples collected from Ulm, Langenau, and Blaubeuren, southern Germany between June to October 2000 at concentrations ranging from 0.20 to 2.1, average/median 0.30; 17-alpha-estradiol was detected in 1 of 10 samples, concentration of 0.30 ng/L(3).
(1) Benotti MJ et al; Environ Sci Technol 43: 597-603 (2009)
(2) Boyd GR et al; Sci Total Environ 311: 135-149 (2003)
(3) Kuch HM, Ballschmiter K; Environ Sci Technol 35: 3201-206 (2001)
SURFACE WATER: 17beta-Estradiol concentrations were reported at a 10.0% frequency with a maximum concentration of 0.093 ug/L and median 0.009 ug/L, in 70 of 139 U.S. streams sampled from 1999-2000 as part of the USGS National Reconnaissance Study(1). 17alpha- and 17beta-Estradiol was detected at maximum concentrations of 25 and 1.7 ng/L in 31 and 18, respectively, of 89 water samples from 30 rangeland grazing areas in Stanislaus, Marin, and Sonoma counties in central California, between April 2005 and March 2006. 17beta-Estradiol was detected in 6% of 32 samples collected near dairy farms, with a maximum concentration of 0.7 ng/L(2). The compound was tested for but not detected (detection limit = 0.1 ng/L) in Mississippi River and Lake Pontchartrain surface water samples collected from New Orleans, Louisiana between September and November, 2001(3). The compound was tested for but not detected in the Eleven Point and North Fork of the White Rivers in Missouri, sampled from August 2003 through November 2004; detection limit = 1.3 ng/L(4). Estradiol was not detected in samples from the West Prong Little Pigeon River in east Tennessee, USA; detection limit = 44 ng/L(5). Concentrations in surface waters worldwide were reported as follows: Japan, 109 major rivers,
(1) Kolpin DW et al; Environ Sci Technol 36: 1202-11 (2002)
(2) Kolodziej EP, Sedlak DL; Environ Sci Technol 41: 3514-3520 (2007)
(3) Boyd GR et al; Sci Total Environ 311: 135-149 (2003)
(4) Solis ME et al; Arch Environ Contam Toxicol 53: 426-434 (2007)
(5) Yu C, Chu K; Chemosphere 75: 1281-1286 (2009)
(6) Ying GG et al; Environ Int 28: 545-551 (2002)
(7) Lei B et al; Chemosphere 76: 36-42 (2009)
(8) Kuch HM, Ballschmiter K; Environ Sci Technol 35: 3201-206 (2001)
(9) Thomas KV et al; Environ Toxicol Chem 20: 2165-70 (2001)
SEAWATER: Concentrations of estradiol in coastal/estuarine water and rivers of The Netherlands (11 locations) ranged from <0.3 to 5.5 ng/L (<0.3 ng/L median)(1). Estradiol concentrations were reported as 23.6, 4.4, and 3.1 ng 17beta estradiol equivalents/L located at, downstream, and upstream from the Howdon sewage treatment works on the Tyne estuary, UK. Estradiol concentrations were reported as 6.3, 0.5, and 0.3 ng 17beta estradiol equivalents/L located at, downstream, and upstream from the Dabholm Gut on the Tees estuary, UK, sampled in 1998(2).
(1) Ying GG et al; Environ Int 28: 545-551 (2002)
(2) Thomas KV et al; Environ Toxicol Chem 20: 2165-70 (2001)

13.2.12 Effluent Concentrations

17beta-Estradiol was reported in 32% of 95-144 samples of central California municipal waste water treatment plant effluent with a maximum concentration of 7.8 ng/L(1). The compound was tested for but not detected (detection limit = 0.1 ng/L) in effluent samples collected from the Jefferson Parish East Bank Wastewater Treatment Plant in New Orleans, Louisiana between September and November, 2001. It was not detected in effluent samples collected during the same time from the A.H. Weeks Water Treatment Plant and the ENWIN Pilot Plant in Windsor, Ontario, Canada(2). Estradiol was not detected in effluent samples from wastewater treatment plants located on the West Prong Little Pigeon River in east Tennessee, USA; detection limit = 44 ng/L(3).
(1) Kolodziej EP, Sedlak DL; Environ Sci Technol 41: 3514-3520 (2007)
(2) Boyd GR et al; Sci Total Environ 311: 135-149 (2003)
(3) Yu C, Chu K; Chemosphere 75: 1281-1286 (2009)
A concentration of 0.0011 ug/L has been reported in effluent from a Swedish sewage treatment plant(1). The mean 17beta-estradiol concentration in effluent samples from a large coastal primary sewage treatment plant in Malabar, Sydney, Australia was 14 ng/L(2). Concentrations in sewage treatment plant effluents were as follows: Italy, 10/99-03/2000, 30 samples, 0.44-3.3 ng/L (1.0 ng/L median); Netherlands, 10/97-12/97, 6 samples, <0.1-5.0 ng/L (
(1) Carlsson C et al; Sci Total Environ 364: 67-87 (2006)
(2) Braga O et al; Chemosphere 61: 827-833 (2005)
(3) Ying GG et al; Environ Int 28: 545-551 (2002)
(4) Kuch HM, Ballschmiter K; Environ Sci Technol 35: 3201-206 (2001)
(5) Mispagel C et al; Arch Environ Contam Toxicol 56: 631-637 (2009)
(6) Sole M et al; Environ Sci Technol 34: 5076-5083 (2000)
(7) Ternes T; in Amer Chem Soc, ASC Symp Ser 2001, 791(Pharmaceuticals and Personal Care Products in the Environment): 39-54 (2001)
17alpha-Estradiol was detected in a typical dairy waste disposal system for 2000 dairy cows in San Jacinto, CA (ug/kg dry weight): fresh manure less than 2 hrs old, 1416; piled manure at 2 weeks, 172; three lagoon days at 3 months; 43, 54, and 8, respectively. Concentrations reported for 17beta-estradiol were 153 in fresh manure, 37 in piled manure, 18 ug/kg dry weight in dam 1, below the detection limit in dam 2, and not detected in dam 3(1). A concentration of 3 ng/L was estimated as present in runoff from agricultural fields in the Calleguas Creek watershed, Ventura County, CA which have been irrigated with treated wastewater; concentration in applied wastewater ranged from 0.1-64 ng/L(2).
(1) Zheng W et al; Environ Sci Technol 42: 530-535 (2008)
(2) Pedersen JA et al; J Agric Food Chem 53: 1625-1632 (2005)
As a result of analysis of effluents of several different types of municipal waste treatment plants in central Michigan, it has been concluded that human hormones (17beta-estradiol) and synthetic hormones (ethinylestradiol), not industrial chemicals with estrogenic activity, in the effluents caused male fish to produce vitellogenin, an accepted indicator of endocrine disruption(1).
(1) Geyer HJ et al; Bioaccumulation and occurrence of endocrine-disrupting chemicals (EDCs), persistent organic pollutants (POPs), and other organic compounds in fish and other organisms including humans. In: Handb. Environ. Chem., Vol. 2, pt. J, Beek B, ed., Berlin, Germany: Spring-Verlag pp. 1-166 (2002)

13.2.13 Sediment / Soil Concentrations

SEDIMENT: Estradiol was detected in ocean surficial sediment samples at a range of 0.22 to 2.48 ng/g; samples were collected near a discharge point from a large coastal primary sewage treatment plant in Malabar, Sydney, Australia(1). Levels of estradiol in sediment from the Beitang River, Dagu River, and Yongding New River in the Tianjin area, northern China, sampled in June 2007 were 0.71-9.60, 1.60-9.23, and not detected-5.63 ng/g dry weight, respectively, with mean concentrations of 5.28, 4.40 and 3.34 ng/g dry weight, respectively(2). The concentration of estradiol in estuarine sediments in Jamaica Bay, NY impacted by sewage outflow from six wastewater treatment plants ranged from 0.05-0.53 ng/g; detection limit 0.04 ng/g and samples were collected in summer, 1998(3).
(1) Braga O et al; Chemosphere 61: 827-833 (2005)
(2) Lei B et al; Chemosphere 76: 36-42 (2009)
(3) Reddy S, Brownawell BJ; Environ Toxicol Chem 24: 1-41-1047 (2005)

13.2.14 Animal Concentrations

Mean estradiol concentrations of 2.70 and 4.36 ng/g dry weight were reported in eggs of the great crested grebe (Podiceps critatus) from Lakes Maggiore and Garda, respectively, northern Italy, sampled from 2001-2005(1).
(1) Cortinovis S et al; Chemosphere 73: 320-325 (2008)

13.2.15 Milk Concentrations

ENVIRONMENTAL: Free natural estrogens in raw and commercial whole milk were quantitated by radioimmunoassay. The concentration range of estradiol 17-beta was 4 to 14 pg/mL. The proportions of active estradiol in the fat phases of milk by radioactive tracer on separated milk was 65%. Equilibrium dialysis of skim milk with hydrogen 3-labeled estrogens showed that 84 to 85% of estradiol was protein bound. Whey proteins demonstrated a greater binding capacity than casein. This result was confirmed by radioimmunoassay of dry curd cottage cheese and whey. The concentration in curd was 11 pg/g and in whey 2 pg/mL. Butter was highest with a concentration of 82 pg/g. Human colostrum demonstrated a maximum concentration of 4 to 5 ng/mL for estriol. By the 5th day postpartum, it decreased to become similar to cow's milk.
Wolford ST, Argoudelis CJ; J Dairy Sci 62(9): 1458-63 (1979). Available from, as of Aug 10, 2011: https://www.sciencedirect.com/science/article/pii/S0022030279834463
EXPERIMENTAL: Estrogens are excreted in milk. Potential for decreased milk volume and decreased nitrogen and protein content ...
Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 45-25
EXPERIMENTAL: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Estradiol Transdermal System Continuous Delivery (Once-Weekly) is administered to a nursing woman.
US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806

13.2.16 Other Environmental Concentrations

Human excretion of estradiol may be as high as 5 mg/day. A nonpregnant and pregnant diary cow excretes approximately 0.8-1.2 mg/day and up to 11.4 mg/day of 17alpha-estradiol, respectively. As high as 6 mg estrogenicity as 17beta-estradiol equivalent (EEQ)/per kg dry weight has been found in swine manure(1).
(1) Khanal SK et al; Environ Sci Technol 40: 6537-6546 (2006)

13.2.17 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 9,083 workers (8,217 of these were female) were potentially exposed to estradiol in the US(1). Occupational exposure to estradiol may occur through inhalation and dermal contact with this compound at workplaces where estradiol is produced or used. Exposure to estradiol via ingestion will occur when administered drugs containing this compound. Monitoring data indicate that the general population may be exposed to estradiol at well below the therapeutic dose via ingestion of drinking water and dermal contact with contaminated sediments(SRC).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of Jan 11, 2011: https://www.cdc.gov/noes/

13.2.18 Body Burden

... Human colostrum demonstrated a maximum concentration of about .5 ng/mL for estradiol. By the 5th day postpartum, it decreased to become similar to cow's milk.
Wolford ST, Argoudelis CJ; J Dairy Sci 62(9): 1458-63 (1979). Available from, as of Aug 10, 2011: https://www.sciencedirect.com/science/article/pii/S0022030279834463

14 Associated Disorders and Diseases

Disease
Menstrual cycle
References
The Merck Manual, 17th ed. Mark H. Beers, MD, Robert Berkow, MD, eds. Whitehouse Station, NJ: Merck Research Labs, 1999.
Disease
Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency
References
Disease
Aromatase deficiency
References
PubMed: 9177373
Disease
Congenital Adrenal Hyperplasia, due to 17-Hydroxylase-Deficiency
References
Disease
X-linked ichthyosis
References
PubMed: 3864567
Disease
Lipoid Congenital Adrenal Hyperplasia
References
Disease
Proprotein Convertase 1/3 Deficiency
References
PubMed: 7477119
Disease
Benign gynecological diseases
References
PubMed: 10585175

15 Literature

15.1 Consolidated References

15.2 NLM Curated PubMed Citations

15.3 Springer Nature References

15.4 Thieme References

15.5 Wiley References

15.6 Nature Journal References

15.7 Chemical Co-Occurrences in Literature

15.8 Chemical-Gene Co-Occurrences in Literature

15.9 Chemical-Disease Co-Occurrences in Literature

16 Patents

16.1 Depositor-Supplied Patent Identifiers

16.2 WIPO PATENTSCOPE

16.3 FDA Orange Book Patents

16.4 FDA Green Book Patents

16.5 Chemical Co-Occurrences in Patents

16.6 Chemical-Disease Co-Occurrences in Patents

16.7 Chemical-Gene Co-Occurrences in Patents

17 Interactions and Pathways

17.1 Protein Bound 3D Structures

17.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

17.2 Chemical-Target Interactions

17.3 Drug-Drug Interactions

17.4 Pathways

18 Biological Test Results

18.1 BioAssay Results

19 Taxonomy

Zebrafish Pathway Metabolite MetFrag Local CSV (Beta) | DOI:10.5281/zenodo.3457553
The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

20 Classification

20.1 MeSH Tree

20.2 NCI Thesaurus Tree

20.3 ChEBI Ontology

20.4 LIPID MAPS Classification

20.5 KEGG: Metabolite

20.6 KEGG: Lipid

20.7 KEGG: Drug

20.8 KEGG: USP

20.9 KEGG: ATC

20.10 KEGG: Target-based Classification of Drugs

20.11 KEGG: Risk Category of Japanese OTC Drugs

20.12 KEGG: OTC drugs

20.13 KEGG: Drug Groups

20.14 KEGG: Drug Classes

20.15 WHO ATC Classification System

20.16 FDA Pharm Classes

20.17 ChemIDplus

20.18 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

20.19 ChEMBL Target Tree

20.20 UN GHS Classification

20.21 EPA CPDat Classification

20.22 NORMAN Suspect List Exchange Classification

20.23 CCSBase Classification

20.24 EPA DSSTox Classification

20.25 LOTUS Tree

20.26 FDA Drug Type and Pharmacologic Classification

20.27 EPA Substance Registry Services Tree

20.28 MolGenie Organic Chemistry Ontology

21 Information Sources

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    Estra-1,3,5(10)-triene-3,17-diol, (17.beta.)-
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    https://creativecommons.org/licenses/by-nc/4.0/
    Estra-1,3,5(10)-triene-3,17-diol (17β)-, (±)-
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    https://www.cancer.gov/policies/copyright-reuse
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  29. DailyMed
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  40. FDA Orange Book
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