Identification

Name
Thimerosal
Accession Number
DB11590
Type
Small Molecule
Groups
Approved
Description

Thiomersal (INN), commonly known in the U.S. as thimerosal, is an organomercury compound. This compound is a well-established and widely used antiseptic and antifungal agent.

Developed in 1927, thimerosal has been and is still being used as a preservative in some cosmetics, topical pharmaceuticals, and biological drug products, which includes vaccines. There has been significant concern regarding its safety and toxicity in the last several decades. Although thimerosal is banned in several countries, it continues to be included as a preservative in some vaccines in the United States and many vaccines in the developing world [17].

Structure
Thumb
Synonyms
  • [(o-carboxyphenyl)thio]ethylmercury sodium salt
  • ethyl(2-mercaptobenzoato-S)mercury sodium salt
  • ethylmercurithiosalicylate sodium
  • ethylmercurithiosalicylic acid sodium salt
  • mercurothiolate
  • o-(ethylmercurithio)benzoic acid sodium salt
  • sodium ethylmercurithiosalicylate
  • sodium merthiolate
  • Thiomersal
  • thiomersalate
  • Thiomersalum
  • Tiomersal
Active Moieties
NameKindUNIICASInChI Key
Ethylmercurithiosalicylic acidunknown4071N4J64W148-61-8HXQVQGWHFRNKMS-UHFFFAOYSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
T.R.U.E. Test Thin-Layer Rapid Use Patch TestThimerosal (6 ug/48h) + 2,2'-Dibenzothiazyl disulfide (20 ug/48h) + 2-mercaptobenzothiazole (61 ug/48h) + 4-(Isopropylamino)diphenylamine (10 ug/48h) + Bacitracin (486 ug/48h) + Balsam of Peru (648 ug/48h) + Benzocaine (378 ug/48h) + Benzylparaben (162 ug/48h) + Bisphenol A diglycidyl ether (32 ug/48h) + Bromothalonil (4 ug/48h) + Bronopol (203 ug/48h) + Budesonide (0.8 ug/48h) + Butylparaben (162 ug/48h) + Chlorquinaldol (77 ug/48h) + Cinchocaine hydrochloride (66 ug/48h) + Cinnamaldehyde (41 ug/48h) + Cinnamyl alcohol (63 ug/48h) + Clioquinol (77 ug/48h) + Cobalt chloride hexahydrate (4 ug/48h) + Diazolidinylurea (446 ug/48h) + Potassium dichromate (15.7 ug/48h) + Dipentamethylenethiuram disulfide (5.5 ug/48h) + Diphenylguanidine (68 ug/48h) + Disperse Blue 106 (41 ug/48h) + Disulfiram (5.5 ug/48h) + Ditiocarb Zinc (68 ug/48h) + Ethyl hydroxybenzoate (162 ug/48h) + Ethylenediamine (18 ug/48h) + Eugenol (41 ug/48h) + Evernia prunastri (81 ug/48h) + Formaldehyde (146 ug/48h) + Geraniol (81 ug/48h) + Hydrocortisone butyrate (16 ug/48h) + Hydroxycitronellal (63 ug/48h) + Imidurea (486 ug/48h) + Isoeugenol (17 ug/48h) + Lanolin alcohols (810 ug/48h) + Methylchloroisothiazolinone (3 ug/48h) + Methylparaben (162 ug/48h) + Morpholinylmercaptobenzothiazole (20 ug/48h) + N,N'-diphenyl-1,4-phenylenediamine (25 ug/48h) + N-Cyclohexyl-N'-phenyl-1,4-phenylenediamine (25 ug/48h) + Neomycin sulfate (486 ug/48h) + Nickel sulfate hexahydrate (36 ug/48h) + P-Tert-Butylphenol-Formaldehyde Resin (Low Molecular Weight) (36 ug/48h) + Parthenolide (2 ug/48h) + Propylparaben (162 ug/48h) + Quaternium-15 (81 ug/48h) + Rosin (972 ug/48h) + Sodium aurotiosulfate (23 ug/48h) + Tetracaine hydrochloride (66 ug/48h) + Tetramethylthiuram monosulfide (5.5 ug/48h) + Thiohexam (20 ug/48h) + Thiram (5.5 ug/48h) + Tixocortol pivalate (2 ug/48h) + Zinc Dibutyldithiocarbamate (68 ug/48h) + alpha-Amyl cinnamaldehyde (17 ug/48h) + p-Phenylenediamine (65 ug/48h)KitSmartPractice Denmark ApS2012-03-01Not applicableUs
International/Other Brands
Mersol
Categories
UNII
2225PI3MOV
CAS number
54-64-8
Weight
Average: 404.81
Monoisotopic: 405.992720501
Chemical Formula
C9H9HgNaO2S
InChI Key
RTKIYNMVFMVABJ-UHFFFAOYSA-L
InChI
InChI=1S/C7H6O2S.C2H5.Hg.Na/c8-7(9)5-3-1-2-4-6(5)10;1-2;;/h1-4,10H,(H,8,9);1H2,2H3;;/q;;2*+1/p-2
IUPAC Name
ethyl({2-[(sodiooxy)carbonyl]phenyl}sulfanyl)mercury
SMILES
CC[Hg]SC1=CC=CC=C1C(=O)O[Na]

Pharmacology

Indication

Used as preservative in some cosmetics, topical pharmaceuticals, and biological drug products, which includes vaccines [3, 4, 5].

Pharmacodynamics

Thimerosal is an organomercurial compound and derivative of thiosalicyclic acid with antibacterial and antifungal properties [4]. Thimerosal, which consists of approximately 50% mercury by weight, has been one of the most widely used preservatives in vaccines. It is metabolized/degraded to ethylmercury and thiosalicylate. Ethylmercury is an organomercurial that must be carefully distinguished from methylmercury, a closely related substance that has been the focus of many studies. Methylmercury is the type of mercury found in various species of fish [20]. Experimental data demonstrates that the toxicokinetics of thimerosal (ethylmercury) is vastly different from that of methyl-mercury. Thus, methyl-mercury is not a suitable reference for assessing the risk from exposure to thimerosal-derived mercury [23].

Prior to the recent initiative to reduce or eliminate thimerosal from childhood vaccines, the maximum cumulative exposure to mercury via routine childhood vaccinations during the first 6 months of life was 187.5 micrograms. In the most recently formulated vaccines, the maximum cumulative exposure during the first 6 months of life should now be less than 3 micrograms of mercury. Currently, thimerosal may still be used in the early stages of manufacturing of certain childhood vaccines, however, only a trace remains after a chemical purification process. Note that the dose above is indicated for children 1-6 months of age is applicable only in the United States, and other countries may have varying indications [19].

Mechanism of action

Although its mechanism of action is not fully understood, thimerosal inhibits sulfhydryl-containing active site of various enzymes and binds to sulfhydryl compounds, including glutathione, cysteine, and sulfhydryl groups of proteins. In addition, thimerosal activates the InsP3 calcium channel on the endoplasmic reticular membrane, thereby triggering the release of intracellular calcium resulting in a calcium-induced calcium-influx of extracellular calcium. Therefore, thimerosal may induce or inhibit various cellular functions that are dependent on the signaling of calcium [6].

Ethylmercury is metabolized to inorganic mercury more rapidly than methylmercury. This difference in metabolism may account for kidney pathology that can result from toxic quantities. Also, whereas the increase in oxidative stress and induction of apoptosis observed in vitro with large doses (405 μg/L to 101 mg/L) of thimerosal may explain its damaging neurological effects. The effects of low-dose ethylmercury are not completely understood to date. It is known, however, that the shorter half-life of ethylmercury (the metabolite of thimerosal) allows for very limited opportunities of ethylmercury derived from thimerosal in vaccines [6].

Ethylmercury is a lipophilic cation that is capable of crossing the blood-brain barrier. The octanol/water partition coefficients of methyl and ethylmercury are 1.4 to 1.8, at intracellular pH and [Cl−], therefore, both organomercury compounds will primarily exist as intracellular lipophilic cations. It has been demonstrated that lipophilic cations accumulate inside mitochondria, in a Nernstian fashion, driven by the steady state membrane potential. As the typical mitochondrial membrane potential of astrocytes and neurons is between 140–170 mV, one would expect the concentration of these organomercury compounds within mitochondria to be approximately 1000 times greater than the cytosolic concentration [21].

TargetActionsOrganism
UMethionine synthase
antagonist
Human
UCystine/glutamate transporter
antagonist
Human
USodium/potassium-transporting ATPase subunit gamma
antagonist
Human
Absorption

Less than 0.01% of an ingested dose is absorbed from the GI tract (rat study) [19].

Volume of distribution

266 L in one study [10]

Protein binding

95 to 99% (depending on animal species and experimental conditions) of the mercury in plasma is bound to albumin (along with other plasma proteins). As significant proportion of albumin is filtered at the glomerulus [24].

Metabolism

Ethylmercury (etHg) is derived from the metabolism of thimerosal (o-carboxyphenyl-thio-ethyl-sodium salt), which is the most widely used form of organic mercury [1].

Route of elimination

Gastrointestinal tract [7].

Half life

A study was done to study the pharmacokinetics of Thimerosal in mice. Estimated half-lives (in days) were 8.8 for blood, 10.7 for brain, 7.8 for heart, 7.7 for liver and 45.2 for kidney [17].

The the long half-life of ethylmercury (~50 days on average in humans) results in accumulation that may be harmful to the developing fetal brain, as it is more susceptible to organomercurial compounds than the adult brain [19].

Clearance

The high concentrations of mercury identified in stool samples suggest that ethylmercury may be eliminated through the gastrointestinal tract [7].

Toxicity

Ld50 Oral: 75 mg/kg (mouse), 91 mg/kg (mouse) [25]

Although methylmercury (meHg) is considered a hazardous substance that is to be avoided even at small levels when consumed in foods such as seafood and rice (in Asia), the World Health Organization considers small doses of thimerosal safe regardless of multiple/repetitive exposures to vaccines that are predominantly taken during pregnancy or infancy [17, 18, 21].

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Dorea JG, Farina M, Rocha JB: Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury. J Appl Toxicol. 2013 Aug;33(8):700-11. doi: 10.1002/jat.2855. Epub 2013 Feb 11. [PubMed:23401210]
  2. Hussain S, Atkinson A, Thompson SJ, Khan AT: Accumulation of mercury and its effect on antioxidant enzymes in brain, liver, and kidneys of mice. J Environ Sci Health B. 1999 Jul;34(4):645-60. doi: 10.1080/03601239909373219. [PubMed:10390852]
  3. Thimerosal and Vaccines [Link]
  4. Thimerosal, Pubchem [Link]
  5. Questions about Vaccines [Link]
  6. 54-64-8(Thimerosal) Product Description [Link]
  7. Thimerosal-Containing Vaccines and Autism: A Review of Recent Epidemiologic Studies [Link]
  8. Toxic Effects of Mercury on the Cardiovascular and Central Nervous Systems [Link]
  9. Thimerosal [54-64-8] [Link]
  10. Toxicokinetics of Mercury after Long-Term Repeated Exposure to Thimerosal-Containing Vaccine [Link]
  11. https://www.researchgate.net/publication/51732698_Administration_of_Thimerosal_to_Infant_Rats_Increases_Overflow_of_Glutamate_and_Aspartate_in_the_Prefrontal_Cortex_Protective_Role_of_Dehydroepiandrosterone_Sulfate [Link]
  12. Thimerosal, an overview [Link]
  13. Thimerosal in Flu Vaccine [Link]
  14. Thimerosal and Animal Brains: New Data for Assessing Human Ethylmercury Risk [Link]
  15. Thimerosal: Clinical, epidemiologic and biochemical studies [Link]
  16. The Thimerosal Controversy [Link]
  17. A systematic study of the disposition and metabolism of mercury species in mice after exposure to low levels of thimerosal (ethylmercury) [Link]
  18. Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury [Link]
  19. Mercury [Link]
  20. The toxicology of Mercury [Link]
  21. The Toxicology of Mercury [Link]
  22. Sigma Aldrich Thimerosal [Link]
  23. Identification and distribution of mercury species in rat tissues following administration of Thimerosal or methylmercury [Link]
  24. Molecular Interactions with Mercury in the Kidney [Link]
  25. Material Safety Data Sheet Thimerosal MSDS [Link]
External Links
KEGG Drug
D00864
PubChem Compound
16684434
PubChem Substance
347827997
ChemSpider
5697
ChEBI
9546
ChEMBL
CHEMBL508338
Wikipedia
Thiomersal
ATC Codes
D08AK06 — Thiomersal

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)-38.87 http://scorecard.goodguide.com/chemical-profiles/html/mercury.html
boiling point (°C)357.3https://www.canada.ca/en/environment-climate-change/services/pollutants/mercury-environment/about/chemical-properties.html
water solubility1 g/mLhttps://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/1/t5125pis.pdf
Predicted Properties
PropertyValueSource
Water Solubility6.17 mg/mLALOGPS
logP2.58ALOGPS
logP3.26ChemAxon
logS-1.8ALOGPS
pKa (Strongest Basic)-6.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area26.3 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity48.06 m3·mol-1ChemAxon
Polarizability22.45 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
13C NMR Spectrum1D NMRNot Applicable

Taxonomy

Description
This compound belongs to the class of organic compounds known as o-sulfanylbenzoic acids. These are benzoic acids which bear a sulfanyl group (R-SH) attached to the benzene ring at positions 1 and 2, respectively.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
O-sulfanylbenzoic acids
Alternative Parents
Benzoic acids / Benzoyl derivatives / Monocarboxylic acids and derivatives / Carboxylic acids / Transition metal alkyls / Organosulfur compounds / Organooxygen compounds / Organic salts / Organic oxides / Hydrocarbon derivatives
show 1 more
Substituents
O-sulfanylbenzoic acid / Benzoic acid / Benzoyl / Carboxylic acid derivative / Carboxylic acid / Monocarboxylic acid or derivatives / Organic oxygen compound / Organosulfur compound / Organooxygen compound / Organometallic compound
show 8 more
Molecular Framework
Not Available
External Descriptors
alkylmercury compound (CHEBI:9546)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofola...
Gene Name
MTR
Uniprot ID
Q99707
Uniprot Name
Methionine synthase
Molecular Weight
140525.91 Da
References
  1. Sigma Aldrich Thimerosal [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Cystine:glutamate antiporter activity
Specific Function
Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for anionic form of cystine and glutamate.
Gene Name
SLC7A11
Uniprot ID
Q9UPY5
Uniprot Name
Cystine/glutamate transporter
Molecular Weight
55422.44 Da
References
  1. Sigma Aldrich Thimerosal [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Transporter activity
Specific Function
May be involved in forming the receptor site for cardiac glycoside binding or may modulate the transport function of the sodium ATPase.
Gene Name
FXYD2
Uniprot ID
P54710
Uniprot Name
Sodium/potassium-transporting ATPase subunit gamma
Molecular Weight
7283.265 Da
References
  1. Sigma Aldrich Thimerosal [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Nadp binding
Specific Function
Maintains high levels of reduced glutathione in the cytosol.
Gene Name
GSR
Uniprot ID
P00390
Uniprot Name
Glutathione reductase, mitochondrial
Molecular Weight
56256.565 Da
References
  1. Hussain S, Atkinson A, Thompson SJ, Khan AT: Accumulation of mercury and its effect on antioxidant enzymes in brain, liver, and kidneys of mice. J Environ Sci Health B. 1999 Jul;34(4):645-60. doi: 10.1080/03601239909373219. [PubMed:10390852]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Sh3 domain binding
Specific Function
Protects the hemoglobin in erythrocytes from oxidative breakdown.
Gene Name
GPX1
Uniprot ID
P07203
Uniprot Name
Glutathione peroxidase 1
Molecular Weight
22087.94 Da
References
  1. Hussain S, Atkinson A, Thompson SJ, Khan AT: Accumulation of mercury and its effect on antioxidant enzymes in brain, liver, and kidneys of mice. J Environ Sci Health B. 1999 Jul;34(4):645-60. doi: 10.1080/03601239909373219. [PubMed:10390852]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Superoxide dismutase activity
Specific Function
Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.
Gene Name
SOD2
Uniprot ID
P04179
Uniprot Name
Superoxide dismutase [Mn], mitochondrial
Molecular Weight
24721.955 Da
References
  1. Stephenson GA, Stowell JG, Toma PH, Pfeiffer RR, Byrn SR: Solid-state investigations of erythromycin A dihydrate: structure, NMR spectroscopy, and hygroscopicity. J Pharm Sci. 1997 Nov;86(11):1239-44. [PubMed:9383733]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Wu X, Liang H, O'Hara KA, Yalowich JC, Hasinoff BB: Thiol-modulated mechanisms of the cytotoxicity of thimerosal and inhibition of DNA topoisomerase II alpha. Chem Res Toxicol. 2008 Feb;21(2):483-93. doi: 10.1021/tx700341n. Epub 2008 Jan 16. [PubMed:18197631]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Phosphatidylinositol binding
Specific Function
Intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5-trisphosphate. Involved in the regulation of epithelial secretion of elect...
Gene Name
ITPR1
Uniprot ID
Q14643
Uniprot Name
Inositol 1,4,5-trisphosphate receptor type 1
Molecular Weight
313926.375 Da

Drug created on April 28, 2016 21:00 / Updated on November 02, 2018 07:12