| Thiomersal | |
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Ethyl(2-mercaptobenzoato-(2-)-O,S) |
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Other names
Mercury((o-carboxyphenyl)thio)ethyl sodium salt |
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| Identifiers | |
| CAS number | 54-64-8 |
| ChemSpider | 10772045 |
| UNII | 2225PI3MOV |
| EC number | 200-210-4 |
| ChEBI | CHEBI:9546 |
| ChEMBL | CHEMBL508338 |
| RTECS number | OV8400000 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C9H9HgNaO2S |
| Molar mass | 404.81 g/mol |
| Appearance | White or slightly yellow powder |
| Density | 2.508 g/cm³[1] |
| Melting point |
232–233 °C (decomposition) |
| Solubility in water | 1000 g/l (20 °C) |
| Hazards | |
| MSDS | External MSDS |
| EU classification | Very toxic (T+) Dangerous for the environment (N) Repr. Cat. 1 |
| R-phrases | R26/27/28 R33 R50/53 |
| S-phrases | S13 S28 S36 S45 S60 S61 |
| NFPA 704 |
1
3
1
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| Flash point | 250 °C |
| (verify) (what is: /?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| Infobox references | |
Thiomersal (INN), and commonly known in the US as thimerosal, is an organomercury compound. This compound is a well established antiseptic and antifungal agent.
The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate and it has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks. Its use as a vaccine preservative is controversial, and it is being phased out from routine childhood vaccines in the United States, the European Union, and a few other countries.[2]
Contents |
Thiomersal features mercury(II) with a coordination number 2, i.e. two ligands are attached to Hg, the thiolate and the ethyl group. The carboxylate group is not coordinated, but confers solubility in water. Like other two-coordinate Hg(II) compounds, the coordination geometry is linear, with a 180° S-Hg-C angle. Typically, organomercury thiolate compounds are prepared from organomercury chlorides.[1]
Thiomersal's main use is as an antiseptic and antifungal agent. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative.[3] Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects.[4] Bacteriostatics like thiomersal are not needed in more-expensive single-dose injectables.[5]
In the United States, countries in the European Union and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules.[2] In the U.S., the only exceptions among vaccines routinely recommended for children are some formulations of the inactivated influenza vaccine for children older than two years.[6] Several vaccines that are not routinely recommended for young children do contain thiomersal, including DT (diphtheria and tetanus), Td (tetanus and diphtheria), and TT (tetanus toxoid); other vaccines may contain a trace of thiomersal from steps in manufacture.[3] Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal.[7] Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more-expensive single-dose administration.[8]
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).[9] In the body, it is metabolized or degraded to ethylmercury (C2H5Hg+) and thiosalicylate.[3]
Few studies of the toxicity of thiomersal in humans have been performed. Cases have been reported of severe poisoning by accidental exposure or attempted suicide, with some fatalities.[10] Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that the disposition patterns of mercury are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets, with lack of motor coordination being a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-life of about 18 days in adults. Ethylmercury is eliminated from the brain in about 14 days in infant monkeys. Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury.[11] Methylmercury and ethylmercury distributes to all body tissues, crossing the blood-brain barrier and the placental barrier, and ethylmercury also moves freely throughout the body.[12] Concerns based on extrapolations from methylmercury caused thiomersal to be removed from U.S. childhood vaccines, starting in 1999. Since then, it has been found 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.[11] 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.[11]
Thiomersal is used in patch testing for people who have dermatitis, conjunctivitis, and other potentially allergic reactions. A 2007 study in Norway found that 1.9% of adults had a positive patch test reaction to thiomersal;[13] a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.[14] Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization,[15] so contact allergy is usually clinically irrelevant.[14] Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.[16] 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 have received six thiomersal-preserved vaccines during their life course, with the last immunization taking place 2–3 years before the mentioned study, younger children received only four thiomersal-preserved vaccines, with the last one applied 5 years before the study, while further immunizations were performed with new thiomersal-free vaccines.[17]
Following a review of mercury-containing food and drugs mandated in 1999, the Centers for Disease Control (CDC) and the American Academy of Pediatrics asked vaccine manufacturers to remove thiomersal from vaccines as a purely precautionary measure, and it was rapidly phased out of most U.S. and European vaccines.[4][18] Many parents took 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.[4] The current scientific consensus is that no convincing scientific evidence supports these claims, based on various lines of evidence including the observation that the rate of autism continues to climb despite elimination of thiomersal from routine childhood vaccines.[19][20][21] Major scientific and medical bodies such as the Institute of Medicine[21] and World Health Organization[22] as well as governmental agencies such as the Food and Drug Administration[3] and the CDC[23] reject any role for thiomersal in autism or other neurodevelopmental disorders.[24] This controversy has caused harm due to parents attempting to treat their autistic children with unproven and possibly dangerous treatments, discouraging parents from vaccinating their children due to fears about thiomersal toxicity[25] and diverting resources away from research into more promising areas for the cause of autism.[26] Thousands of lawsuits have been filed in a U.S. federal court to seek damages from alleged toxicity from vaccines, including those purportedly caused by thiomersal.[27]
Morris Kharasch, a chemist at the University of Maryland, filed a patent application for thiomersal in 1927;[28] Eli Lilly later marketed the compound under the trade name Merthiolate.[4] In vitro tests conducted by Lilly investigators H. M. Powell and W. A. Jamieson found that it was forty to fifty times as effective as phenol against Staphylococcus aureus.[4] It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals, including nasal sprays, eye drops, contact lens solutions, 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.[4]
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