Thiomersal

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Thimerosal
)

Thiomersal
Thiomersal
Names
IUPAC name
Ethyl(2-mercaptobenzoato-(2-)-O,S) mercurate(1-) sodium
Other names
Mercury((o-carboxyphenyl)thio)ethyl sodium salt, sodium ethylmercurithiosalicylate
Identifiers
3D model (
JSmol
)
8169555
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
100.000.192 Edit this at Wikidata
EC Number
  • 200-210-4
1677155
KEGG
RTECS number
  • OV8400000
UNII
  • 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 checkY
    Key: RTKIYNMVFMVABJ-UHFFFAOYSA-L checkY
  • InChI=1/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/rC9H10HgO2S.Na/c1-2-10-13-8-6-4-3-5-7(8)9(11)12;/h3-6H,2H2,1H3,(H,11,12);/q;+1/p-1
    Key: RTKIYNMVFMVABJ-TYXNQWANAP
  • [Na+].[O-]C(=O)c1ccccc1S[Hg]CC
Properties
C9H9HgNaO2S
Molar mass 404.81 g/mol
Appearance White or slightly yellow powder
Density 2.508 g/cm3[1]
Melting point 232 to 233 °C (450 to 451 °F; 505 to 506 K) (decomposition)
1000 g/L (20 °C)
Pharmacology
D08AK06 (WHO)
Hazards
GHS labelling:
GHS06: ToxicGHS08: Health hazardGHS09: Environmental hazard
Danger
H300, H310, H330, H373, H410
P260, P273, P280, P301, P302, P304, P310, P330, P340, P352[2]
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
3
1
1
Flash point 250 °C (482 °F; 523 K)
Lethal dose or concentration (LD, LC):
75 mg/kg (oral, rat)[3]
Safety data sheet (SDS) External MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Thiomersal (

antifungal agent.[5]

The pharmaceutical corporation

called into question by anti-vaccination groups. A statement issued by the American Academy of Pediatrics and the US Public Health Service in 1999 prompted the removal of thimerosal from many vaccines.[11][12] It remains in use as a preservative for annual flu vaccines.[13]

History

immunoglobulins, and vaccines. Thiomersal was used as a preservative (bactericide) so that multidose vials of vaccines could be used instead of single-dose vials, which are more expensive. By 1938, Lilly's assistant director of research listed thiomersal as one of the five most important drugs ever developed by the company.[15]

Structure

Thiomersal features

thiolate and the ethyl group. The carboxylate group confers solubility in water. Like other two-coordinate Hg(II) compounds, the coordination geometry of Hg is linear, with a 180° S-Hg-C angle. Typically, organomercury thiolate compounds are prepared from organomercury chlorides.[1]

Uses

Antiseptic/antifungal

Thiomersal's main use is as an antiseptic and antifungal agent, due to its

Bacteriostatics such as thiomersal are not needed in single-dose injectables.[17]

In the United States, the European Union, and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules.[12] In the U.S., all vaccines routinely recommended for children 6 years of age and younger are available in formulations that do not contain thimerosal. Two vaccines (a TD and the single-dose version of the trivalent influenza vaccine Fluvirin) that may contain a trace of thiomersal from steps in manufacture, but less than 1 microgram of mercury per dose.[16] The multi-dose versions of some trivalent and quadrivalent influenza vaccines can contain up to 25 micrograms of mercury per dose from thiomersal. Also, four rarely used treatments for pit viper, coral snake, and black widow venom contain thiomersal.[18]

Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization reported no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more expensive single-dose administration.[19] The United Nations Environment Program backed away from an earlier proposal of putting thiomersal on the list of banned vaccine compounds as part of its campaign to reduce mercury exposure.[20] It stated that eliminating it in multi-dose vaccines, primarily used in developing countries, would lead to high cost and a refrigeration requirement that developing countries could ill afford. At the Minamata Convention on Mercury in 2013 thiomersal was excluded from the treaty.[21]

Toxicology

General toxicity

Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC hazard symbol T+), with a danger of cumulative effects. It is also very toxic to aquatic organisms and may cause long-term adverse effects in aquatic environments (EC hazard symbol N).[22]

In the body, it is metabolized or degraded to

thiosalicylate.[16]

Cases have been reported of severe mercury poisoning by accidental exposure or attempted suicide, with some fatalities.[23] Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that mercury's disposition patterns are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets. Loss of motor coordination is a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown.[23]

Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a

placental barrier, and ethylmercury also moves freely throughout the body.[26]

Concerns based on extrapolations from methylmercury caused thiomersal to be removed from U.S. childhood vaccines, starting in 1999. Later it was reported that ethylmercury is eliminated from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative.[25] Though inorganic mercury metabolized from ethylmercury has a much longer half-life in the brain, at least 120 days, it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons not yet understood.[25]

As an allergen

Patch test

Thiomersal is used in

subcutaneous immunization,[29] though there have been no large sample sized studies regarding this matter to date. In real-world practice on vaccination of adult populations, contact allergy does not seem to elicit clinical reaction.[28]

Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.[30] In a recent study of Polish children and adolescents with chronic/recurrent eczema, positive reactions to thiomersal were found in 11.7% of children (7–8 y.o.) and 37.6% of adolescents (16–17 y.o.). This difference in the sensitization rates can be explained by changing exposure patterns: The adolescents received six thiomersal-preserved vaccines during their life course, with the last immunization taking place 2–3 years before the study. Younger children received only four thiomersal-preserved vaccines, with the last one applied five years before the study, while further immunizations were performed with thiomersal-free vaccines.[31]

Removal from vaccines

The Center for Biologics Evaluation and Research (CBER) at the FDA initiated a formal risk assessment of thiomersal in vaccines beginning in 1998.[32] After determining the levels of ethylmercury exposure from the currently recommended vaccine schedule, the CBER found these amounts exceeded new standards for methylmercury exposure recently established by the Environmental Protection Agency.[33] On July 7, 1999, both the American Academy of Pediatrics and the US Public Health Service issued a statement calling for the removal of thiomersal-containing vaccines “as expeditiously as possible.”[34][35] By March 2001, thiomersal-free versions of all the recommended childhood vaccines for children up to age 6 were available in the United States following the introduction of the new DtAP vaccine. [36]

Disproven autism hypothesis

Following the phasing out of thiomersal from most U.S. and European vaccines,[15][37] some parents saw the action to remove thiomersal—in the setting of a perceived increasing rate of autism as well as increasing number of vaccines in the childhood vaccination schedule—as indicating that the preservative was the cause of autism.[15] The scientific consensus is that no evidence supports these claims, while the rate of autism continued to climb in children who did not take the thiomersal-preserved childhood vaccines.[9][38][39][40]

Scientific and medical bodies such as the

U.S. federal court to seek damages from allegedly toxic vaccines, including those purportedly caused by thiomersal.[47]

See also

  • Nitromersol – Organomercury antiseptic and antifungal agent, a related antimicrobial
  • Phenylmercuric nitrate – Organomercury compound with powerful antiseptic and antifungal effects

References

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    PMID 18533648
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  2. ^ "Thimerosal T5125".
  3. ^ Chambers, Michael. "ChemIDplus – 54-64-8 – RTKIYNMVFMVABJ-UHFFFAOYSA-L – Thimerosal [USP:JAN] – Similar structures search, synonyms, formulas, resource links, and other chemical information". chem.sis.nlm.nih.gov. Retrieved 3 April 2018.
  4. ^ "Merthiolate poisoning: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 8 December 2023.
  5. ^ "Thimerosal and Vaccines | Vaccine Safety | CDC". Centers for Disease Control and Prevention. 25 August 2020. Retrieved 4 May 2023.
  6. PMID 22811707
    . ...widely used in medical products, including as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks...
  7. ISBN 978-0-309-09237-1.{{cite book}}: CS1 maint: multiple names: authors list (link
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  9. ^ a b "Vaccines Do Not Cause Autism". cdc.gov. Retrieved 29 November 2015.
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  13. ^ "Not Immune". The New Yorker. 8 February 2015. Retrieved 2 October 2022.
  14. ^ U.S. patent 1,672,615 "Alkyl mercuric sulphur compound and process of producing it".
  15. ^
    PMID 18172138
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  16. ^ a b c d "Thimerosal and vaccines". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 2 January 2018. Retrieved 9 April 2023.
  17. Food and Drug Administration
    . Retrieved 9 March 2008.
  18. ^ "Mercury in plasma-derived products". U.S. Food and Drug Administration. 9 September 2004. Archived from the original on 29 September 2007. Retrieved 1 October 2007.
  19. ^ Global Advisory Committee on Vaccine Safety (14 July 2006). "Thiomersal and vaccines". World Health Organization. Archived from the original on 20 August 2003. Retrieved 20 November 2007.
  20. ^ Hamilton, Jon (17 December 2012). "Doctors Argue Against Proposed Ban on Vaccine Preservative". NPR. Retrieved 25 February 2013.
  21. ^ Sulaski Wyckoff, Alyson (22 January 2013). "Global ban on mercury grants exception to thimerosal-containing vaccines". AAP News. American Academy of Pediatrics. Retrieved 24 August 2019.
  22. ^ "Safety data sheet, Thiomersal Ph Eur, BP, USP" (PDF). Merck. 12 June 2005. Archived from the original (PDF) on 15 September 2009. Retrieved 1 January 2010.
  23. ^
    PMID 11834460. Archived from the original
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  33. ^ "One Controversy, Three Histories" Am J Public Health. 2008 February; 98(2):248
  34. ^ “AAP and PHS Urge Reduction of Mercury in Vaccines” Public Health Rep. 1999 Sep-Oct; 114(5): 394–395
  35. ^ "Thimerosal in Vaccines: A Joint Statement of the American Academy of Pediatrics and the Public Health Service" CDC MMWR July 09, 1999 / 48(26);563-565
  36. ^ "Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders" Institute of Medicine (US) National Academies Press (US) 2001.
  37. ^ "Thimerosal in vaccines: frequently asked questions (FAQs)". Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. 7 June 2007. Retrieved 22 July 2008.
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  41. ^ World Health Organization (2006). "Thiomersal and vaccines: questions and answers". Archived from the original on 12 October 2003. Retrieved 19 May 2009.
  42. ^ WHO. "Statement on thiomersal". www.who.int. Archived from the original on 29 October 2012. Retrieved 3 April 2018.
  43. ^ Centers for Disease Control (8 February 2008). "Mercury and vaccines (thimerosal)". Archived from the original on 18 April 2018. Retrieved 19 May 2009.
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