alpha-Naphthylthiourea

α-Naphthylthiourea (ANTU) is an organosulfur compound with the formula C10H7NHC(S)NH2. This a white, crystalline powder although commercial samples may be off-white.[3][2][4] It is used as a rodenticide and as such is fairly toxic. Naphthylthiourea is available as 10% active baits in suitable protein- or carbohydrate-rich materials and as a 20% tracking powder.[8]

α-Naphthylthiourea
Names
IUPAC name
Naphthalen-1-ylthiourea
Other names
1-(1-Naphthyl)-2-thiourea; ANTU; Dirax; 1-Naphthylthiourea; Anturat; Rattrack; Smeesana; Alrato; alpha-Naphthylthiourea; 1-Naphthyl thiourea
Identifiers
3D model (JSmol)
Abbreviations ANTU
ChemSpider
ECHA InfoCard 100.001.552
KEGG
UNII
Properties
C11H10N2S
Molar mass 202.28 g·mol−1
Appearance White solid,[1] crystallizes in prisms from alcohol[2] Colorless, solid. White.[3] White, crystalline or gray powder.[4]
Melting point 197.8 °C (388.0 °F; 470.9 K)
Boiling point Decomposes
600 mg/L
Solubility in other solvents 2.43 g/100mL (acetone)
8.6 g/100mL (triethylene glycol) [2]
log P 1.65 [5]
Vapor pressure 6.6x10−6 mmHg [6]
8.51x10−9 atm-cu m/mol [6]
Hazards
Main hazards Toxic
NFPA 704 (fire diamond)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 4: Very short exposure could cause death or major residual injury. E.g. VX gasReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
4
0
Flash point noncombustible[1]
Lethal dose or concentration (LD, LC):
0.38 mg/kg (dog, oral)
6 mg/kg (rat, oral)
4250 mg/kg (monkey, oral)
5 mg/kg (mouse, oral)[7]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 0.3 mg/m3[1]
REL (Recommended)
 TWA 0.3 mg/m3[1]
IDLH (Immediate danger)
 100 mg/m3[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Synthesis

Like other thioureas, ANTU can be prepared by several routes. The usual method is the reaction of 1-naphthylamine hydrochloride with ammonium thiocyanate:[9]

[C10H7NH3]Cl + NH4SCN → C10H7NHC(S)NH2 + NH3 + HCl

It is produced from the reaction of 1-naphthyl isothiocyanate with ammonia.

C10H7NCS + NH3 → C10H7NHC(S)NH2

Mechanism of action

ANTU is specifically toxic in lung cells due to its conversion to a short-lived active metabolite to which it is converted in the liver, not ANTU acting directly. This damage is focused on the endothelium of pulmonary capillaries and venules, it will lead to the formation of irreversible gaps in the endothelium of pulmonary vessels. This damage can lead to pulmonary edema. In ANTU poisoning plasma, carbon and ferritin escape through a gap in the thick part of the pulmonary capillary into the interstitial tissues of the lung[10]

Toxicity

Alpha-Naphthylthiourea is toxic to inhalation, ingestion, or skin contact, although the intoxication may be delayed. According to the U.S. National Institute for Occupational Safety and Health (NIOSH), the recommended workplace airborne exposure limit is 0.3 mg/m3 averaged over a 10-hour workshift. Exposure to 100 mg/m3 is immediately dangerous to life and health. The lethal dose in humans is approximately 4 g/kg.[11]

Effects on animals

An oral dose of 3 mg per kilogram of body weight causes the death of 50% of the rats exposed (LD50), showing a very high selectivity when compared for example to monkeys ( 4000 mg per kilogram of body weight).[12] However other studies have shown a much higher efficacy for dogs (a LD50 of 0.38 mg/kg).[13]

The mortality of rats caused by 5 mg/kg of ANTU is reduced when allylthiourea, isopropylthiourea, ethylenethiourea, or ethylidenethiourea are administered simultaneously with ANTU.[14] Superoxide dismutase, catalase and dimethylsulfoxide all protect against the lung damage by ANTU (although the results are diverse). This indicates that OH radicals are responsible for this type of lung injury. Given hydroxurea over 2 days doesn't block the ANTU damage when neutrophils are decreased or when administered acutely. Cyclooxygenase pathway may generate the free radicals since ibuprofen blocked as well the ANTU damage.[15]

Toxicity of alpha-Naphthyl thiourea in different animals
OrganismTest typeRouteReported dose
Cat[16]LD50oral500 mg/kg
Chicken[16]LD50intraperitoneal2500 mg/kg
Chicken[16]LD50oral4250 mg/kg
Chicken[17]LD50unreported700 mg/kg
Dog[16]LD50intraperitoneal16 mg/kg
Dog[18]LD50oral0.38 mg/kg
Guinea pig[16]LD50intraperitoneal350 mg/kg
Man[19]LDLounreported588 mg/kg
Monkey[16]LD50intraperitoneal175 mg/kg
Monkey[20]LD50oral4250 mg/kg
Monkey[21]LD50unreported2000 mg/kg
Mouse[22]LD50intraperitoneal10 mg/kg
Mouse[23]LD50oral5 mg/kg
Pig[23]LDLooral50 mg/kg
Rabbit[21]LD50unreported200 mg/kg
Rat[24]LD50intraperitoneal2.47 mg/ kg
Rat[25]LD50oral6 mg/kg

ANTU causes local gastric irritation in animals and when it is absorbed, it increases permeability of the lung capillaries in all animals. The symptoms that the animals present after absorption of alpha-naphthyl thiourea are first weakness, ataxia, weak pulse and subnormal temperatures. Afterwards, they have the following symptoms: vomiting, hypersalivation, coughing and severe pulmonary edema. In the most cases a pale, mottled liver and damaged kidneys are found in animals which have ingested ANTU. Animals with an empty stomach readily vomit after ingestion of this substance. However, when there is food in the stomach of the animals the stimulation to vomit decreases, so more quantities may be absorbed. It has been found that ANTU may cause death in some animals within 2–4 hours of ingestion, while animals that survive 12 hours may recover from the poison.[26] In a long-term, ANTU may cause pulmonary edema and pleural effusion in certain animals, such as rats. Mice treated with alpha-naphthyl thiourea with a dose of 10 mg/kg developed pulmonary edema which was maximal after 3 hours and was resolved by 12 hours. 35 mg/kg of ANTU was caused death to 60% of the animals. It also increases the blood sugar levels in rats.[11] Dogs and pigs are occasionally poisoned with this compound while ruminants are resistant.[26] But when the exposure of this compound in dogs is quite long they may have gastric irritation and respiratory difficulties. Death can then be followed within 6–48 hours depending of the quantity of ANTU ingested.

Metabolism

α-Naphthylthiourea is metabolized by rat liver and lung microsomes to α-naphthylurea (ANU), which is essentially nontoxic to rats with an (LD50 > 800 mg/kg). Conversion of ANTU to ANU requires NADPH. Carbon monoxide inhibits the reaction.[27] There are some evidence of cytochrome P450 being responsible for the bioactivation of ANTU. Therefore, the toxicity of ANTU cannot be explained with the activity of ANU. There are subproducts of this reaction which play an important role in toxicity: atomic sulfur and a metabolic reactive containing the carbon carbonyl of ANTU.[28]

A portion of the atomic sulfur formed in this reaction covalently binds to macromolecules of the liver and lung microsomes. This reaction starts with the formation of sulfhydryl groups of cysteine residues (R-S-H) of different proteins. As a result, the formation of hydrodisulfide complexes takes place (R-S-S-H). This compound is very likely to react with cyanide ions in the cell. Finally, thiocyanate is produced which is a very unstable radical that can lead to cellular damage.[29]

The loss of cytochrome P-450 and monooxygenase activity seen on incubation of liver microsomes with ANTU is likely the result of the covalent binding of atomic sulfur to cytochrome P-450. The available evidence suggests that the pulmonary toxicity of ANTU results, at least in part, from the covalent binding of a cytochrome P-450 monooxygenase catalyzed metabolite of ANTU to pulmonary macromolecules. This metabolite is most likely atomic sulfur or alternatively, the one containing the carbonyl carbon of ANTU. However, it is possible that the binding of both metabolites may be responsible for the lung toxicity.[28]

History

ANTU was developed to combat infestation of rats in the US city of Baltimore, where the increase in population had overwhelmed the sanitation services, causing huge rat-infested garbage piles. Baltimore was also the scene of the discovery of ANTU. In 1942 Curt Richter discovered that phenyl thiourea was lethal, yet tasteless to domesticated rats. This was interesting because a rat's defense against toxins is primarily its sense of taste. However, when Richter started testing the compound in wild rats, it wasn't equally tasteless for them, but had a bitter taste; Richter's lab screened over 200 thiourea compounds to find one equally tasteless and toxic to wild rats. This led to the discovery of ANTU, a compound lethal to rats but non-toxic for humans.

Next Richter set out to test the compound on a large scale. He determined rats won't cross streets and therefore city blocks were used as test areas. Local Boy Scouts volunteered to distribute the poison. When the first tests returned large amounts of dead rats, the tests were extended to a 200-block area with poor housing. The ANTU field trials soon expanded and in 1943 Richter was asked to lead citywide rat control campaign and received funding to replace the Boy Scouts with adult baiters and trappers. Through a joint effort of the city and volunteers about 8400 city blocks were cleaned from May 1943 to mid-1946. After the war ANTU became available to the public, being advertised as a miracle rat killer for households. Richter had however advised against the use of ANTU at a small scale, as rats get a 30-day tolerance for ANTU after a non-lethal dose and become able to detect the chemical. As the rat population returned, the popularity of ANTU decreased. It became clear that more than poisoning alone was needed to get rid of rats. The city of Baltimore soon returned to an environmental approach in rat control and ANTU disappeared from the market after a few years.[30]

References
  1. NIOSH Pocket Guide to Chemical Hazards. "#0037". National Institute for Occupational Safety and Health (NIOSH).
  2. O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 122
  3. Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981., p. 1-2
  4. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases. U.S. Department of Health & Human Services, Public Health Service, Center for Disease Control & Prevention. DHHS (NIOSH) Publication No. 2001-145 (CD-ROM) August 2001
  5. Govers H et al; Chemosphere 15: 383-93 (1986)
  6. US EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Mar 3, 2004: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
  7. "ANTU". Immediately Dangerous to Life and Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH).
  8. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). p. V30 348 (1983)
  9. Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present., p. V16 987 (1995)
  10. Cunningham, A. L., and J. V. Hurley. "Alpha‐naphthyl‐thiourea‐induced pulmonary oedema in the rat: A topographical and electron‐microscope study."The Journal of Pathology 106.1 (1972): 25-35.
  11. Hazardous substance fact sheet- alpha Naphthylthiourea. (2001). In N. J. d. o. h. a. s. services (Ed.).http://nj.gov/health/eoh/rtkweb/documents/fs/0051.pdf (accessed 01-04-14)
  12. Klaassen, C.D. (ed). Casarett and Doull's Toxicology. The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill, 2001., p. 801
  13. Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 260
  14. Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 3. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1289
  15. Marin D et al; Acta Physiol Scand 548: 119-25 (1986)
  16. Proceedings of the Society for Experimental Biology and Medicine. Vol. 62, Pg. 22, 1946.
  17. Chemistry of Pesticides, Melnikov, N.N., New York, Springer-Verlag New York, Inc., 1971Vol. -,Pg. 238, 1971.
  18. Pesticide Chemicals Official Compendium, Association of the American Pesticide Control Officials, Inc., 1966. Vol. -, Pg. 57, 1966.
  19. Poisoning; Toxicology, Symptoms, Treatments, 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas,1970Vol. 2, Pg. 73, 1970.
  20. Wirksubstanzen der Pflanzenschutz und Schadlingsbekampfungsmittel, Perkow, W., Berlin,Verlag Paul Parey, 1971-1976Vol. -, Pg. -, 1971/1976.
  21. Bollettino Chimico Farmaceutico. Vol. 97, Pg. 289, 1958.
  22. National Technical Information Service. Vol. AD277-689
  23. Yakkyoku. Pharmacy. Vol. 28, Pg. 329, 1977.
  24. Journal of Pharmacology and Experimental Therapeutics. Vol. 97, Pg. 432, 1949.
  25. Quarterly Bulletin--Association of Food and Drug Officials of the United States. Vol. 16, Pg. 47,1952.
  26. Merk veterinary manual. (2012) http://www.merckmanuals.com/vet/toxicology/rodenticide_poisoning/antu_%CE%B1-naphthylthiourea.html (accessed 01-04-14)
  27. Boyd, M. R., and Robert A. Neal. "Studies on the mechanism of toxicity and of development of tolerance to the pulmonary toxin, alpha-naphthylthiourea (ANTU)." Drug Metabolism and Disposition 4.4 (1976): 314-322.
  28. Lee, Philip W., Thomas Arnau, and Robert A. Neal. "Metabolism of α-naphthylthiourea by rat liver and rat lung microsomes." Toxicology and Applied Pharmacology 53.1 (1980): 164-173.
  29. Catignani, George L., and Robert A. Neal. "Evidence for the formation of a protein bound hydrodisulfide resulting from the microsomal mixed function oxidase catalyzed desulfuration of carbon disulfide." Biochemical and biophysical research communications 65.2 (1975): 629-636.
  30. Keiner, Christine. "Wartime rat control, rodent ecology, and the rise and fall of chemical rodenticides." Endeavour 29.3 (2005): 119-125
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