| Revision as of 21:42, 10 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,081 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'KEGG').← Previous edit |
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{{chembox |
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{{chembox |
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| verifiedrevid = 396311115 |
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| verifiedrevid = 460032392 |
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|ImageFile=Chlorophacinone.png |
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| ImageFile = Chlorophacinone.svg |
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|ImageSize= |
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| ImageSize = |
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|IUPACName= 2-indane-1,3-dione |
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| PIN = 2--1''H''-indene-1,3(2''H'')-dione |
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|OtherNames= |
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|Section1={{Chembox Identifiers |
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|Section1={{Chembox Identifiers |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 18286 |
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| ChemSpiderID = 18286 |
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| InChI = 1/C23H15ClO3/c24-16-12-10-15(11-13-16)19(14-6-2-1-3-7-14)23(27)20-21(25)17-8-4-5-9-18(17)22(20)26/h1-13,19-20H |
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| InChI = 1/C23H15ClO3/c24-16-12-10-15(11-13-16)19(14-6-2-1-3-7-14)23(27)20-21(25)17-8-4-5-9-18(17)22(20)26/h1-13,19-20H |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo=3691-35-8 |
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| CASNo=3691-35-8 |
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| PubChem=19402 |
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| PubChem=19402 |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG = <!-- blanked - oldvalue: C18514 --> |
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| KEGG = C18514 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 34Y6E0063Y |
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| UNII = 34Y6E0063Y |
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| SMILES = Clc1ccc(cc1)C(c2ccccc2)C(=O)C4C(=O)c3ccccc3C4=O |
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| SMILES = Clc1ccc(cc1)C(c2ccccc2)C(=O)C4C(=O)c3ccccc3C4=O |
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|Section2={{Chembox Properties |
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|Section2={{Chembox Properties |
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| C=23 | H=15 | Cl=1 | O=3 |
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| Formula=C<sub>23</sub>H<sub>15</sub>ClO<sub>3</sub> |
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| MolarMass=374.82 g/mol |
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'''Chlorophacinone''' is a first-generation ] ]. The mechanism of action results in internal bleeding due to non-functional clotting factors. It was used as a toxin to control ] populations. It is classified as an ] in the United States as defined in Section 302 of the U.S. ] (42 U.S.C. 11002) and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.<ref name="gov-right-know">{{Cite journal | publisher = ] | title = 40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities | url = http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | edition = July 1, 2008 | accessdate = October 29, 2011 }}</ref> |
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'''Chlorophacinone''' is an ] used as a ]. |
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==See also== |
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== History == |
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The French company Liphatech (formerly known as Lipha), which had previous experience with creating anticoagulants for the treatment of heart patients, created chlorophacinone in 1961 and branded it “Rozol”. Chlorophacinone belongs to the first-generation anticoagulant rodenticide group, first being developed during the 1940s to 1960s to control rodents in terrestrial environments.<ref>{{Cite web |title=Rodenticides: Background & Hazards {{!}} Safe Rodent Control |url=https://saferodentcontrol.org/site/problems-with-rodenticides/ |access-date=2024-03-14 |language=en-US}}</ref><ref>{{Cite web |title=History |url=https://liphatech.com/history/ |access-date=2024-03-14 |website=liphatech.com |language=en-US}}</ref><ref name=":0">{{Cite web |last=Lemay A, McCaskill M, Warren J, Hall, T.C, Paz L, Deliberto S, Ruell E, Wimberly |date=March 2023 |title=The use of chlorophacinone in Wildlife damage management. |url=https://www.aphis.usda.gov/wildlife_damage/nepa/risk_assessment/26-chlorophacinone.pdf}}</ref> Its use began being replaced during the 1970s, along with the use of other rodenticides of its group, by the more potent second-generation anticoagulant rodenticides, when several studies provided information which depicted a developed resistance of rodents to ] (another first-generation anticoagulant rodenticide) in northern Europe and the United States along with a discovered cross-resistance to all first-generation anticoagulant rodenticides. This was found to be caused by a single, dominant and autosomal gene which raised the rodent's dietary requirement for ] (the vitamin whose production anticoagulants primarily inhibited) to twenty times the normal amount.<ref name=":1">{{Cite web |last=Hadler M, Buckle A |date=1992 |title=Forty Five Years of Anticoagulant Rodenticides - Past, Present and Future Trends |url=https://core.ac.uk/download/pdf/17234624.pdf |page=36}}</ref> Even though its use has diminished, chlorophacinone can still be bought for rodenticide use, for situations in which conventional bait for rodenticidal purposes cannot be used.<ref>{{Cite web |title=Rozol Tracking Powder |url=https://liphatech.com/structural-pest-control/products/rozol-tracking-powder/ |access-date=2024-03-14 |website=liphatech.com |language=en-US}}</ref> |
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* ] |
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== Structure and physical properties == |
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{{rodenticides}} |
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Chlorophacinone is an ] with the following systematic name: (2-indan-1,3-dione. The structure consists of an ], connected on one side to ] ring. Two ]s are attached to the other side, one contains a chloride. Chlorophacinone contains one optically active carbon and therefore it occurs as two ]s. |
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] constant of 5.12 x 10<sup>−7</sup> atm-m3/mol suggests a low potential to volatilize from water or soil into the atmosphere. It is dissolves relatively good in organic solvents like ] (854 mg/L at 25 °C) and ] (786 mg/L at 25 °C), compared to water (3.43 mg/L at 25 °C).<ref name=":0" /><ref name=":2">{{Cite web |date=July 2016 |title=Evaluation of active substances; Renewal of approval; Assessment Report; Chlorophacinone |url=https://www.echa.europa.eu/documents/10162/e623897b-b36e-7527-7ed4-12c9aa311639}}</ref> |
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{| class="wikitable" |
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|Appearance |
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|Pale-yellow powder |
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|Melting point |
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|143.0 °C |
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|Hazard statements |
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|H360D: May damage the unborn child |
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H300: Fatal if swallowed |
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{{ketone-stub}} |
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H310: Fatal in contact with skin |
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] |
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] |
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] |
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] |
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H330: Fatal if inhaled |
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] |
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] |
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H372: Causes damage to the blood through prolonged or |
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repeated exposure |
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H410: Very toxic to aquatic life with long lasting effects |
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|Relative density |
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|1.4301 g/mL |
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|Vapour pressure |
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|4.76 x 10<sup>−4</sup> Pa at 23 °C |
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|Henry's law constant |
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|5.12 x 10<sup>−7</sup> atm-m3/mol |
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|UV/Vis absorption |
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|~260 nm and 315 nm |
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== Synthesis == |
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Chlorophacinone can be synthesized through different mechanisms. A more recently studied mechanism will be discussed below (figure 1). In this synthesizes chlorophacinone is synthesized with less production of side products compared to the classic mechanisms. |
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The synthesis uses ] '''1''' as starting product as it is a cheap and commercially available. Mandelic acid reacts with ] '''2''' in presence of ] to afford 85% of the ] '''3'''. Thereafter, the phenylacetic acid is treated with ] at room temperature to obtain 6-chloro-2,2-diphenylacetyl chloride '''4'''. No purification is needed to start the last step of the synthesis, which is a ] of the previously obtained compound '''4''' with ] '''5'''. This reaction provided the final product, chlorophacinone '''6''', with no significant amount of ] or other side products.<ref>{{Cite journal |last1=Csuk |first1=René |last2=Barthel |first2=Alexander |last3=Ströhl |first3=Dieter |date=2011-01-01 |title=An Alternative and Efficient Route to Chlorophacinone |url=https://www.degruyter.com/document/doi/10.1515/znb-2011-0116/html |journal=Zeitschrift für Naturforschung B |language=en |volume=66 |issue=1 |pages=95–97 |doi=10.1515/znb-2011-0116 |issn=1865-7117|doi-access=free }}</ref> |
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== Mechanism of action == |
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Chlorophacinone is a first-generation anticoagulant rodenticide. The compound is an indandione derivate. It acts as a vitamin K antagonist and exerts its anticoagulatory effect by interfering with the ] synthesis of vitamin K-dependent clotting factors.<ref name=":0" /> Synthesis of clotting factor II, VII, IX and X involves the ] ] of ] to ] by the enzyme γ-glutamyl carboxylase (GGCX). The γ-carboxyglutamate residues promote the binding of clotting factors to ]s of the blood vessels, thereby accelerating ]. However, a vitamin K hydroquinone (KH<sub>2</sub>) ] is needed for the carboxylation reaction to occur. The KH<sub>2</sub> is converted to vitamin K 2,3 epoxide (KO) during the carboxylation reaction. The KH<sub>2</sub> cofactor is created within the vitamin K redox cycle. Chlorophacinone interferes with the vitamin K redox cycle by inhibiting vitamin K epoxide reductase (VKOR), an ] present in the ] (ER). The enzyme plays a vital role within this cycle. The catalytic activity of VKOR is required for the reduction of KO to vitamin K to KH<sub>2</sub>. The inhibition of VKOR by chlorophacinone prevents the recycling of vitamin K from KO to KH<sub>2</sub> (figure 2). Therefore, the supply of KH<sub>2</sub> in the tissue will diminish, this in turn will decrease the carboxylation activity of γ-glutamyl carboxylase.<ref name=":3">{{Cite book |last=Van den Brink NW, Elliott JE, Shore RF, Rattner BA. |title=Anticoagulant Rodenticides and Wildlife |date=2017 |publisher=Springer |pages=87–108}}</ref><ref>{{Citation |last1=Tie |first1=Jian-Ke |title=Structure and Function of Vitamin K Epoxide Reductase |date=2008 |journal=Vitamins & Hormones |volume=78 |pages=103–130 |url=https://linkinghub.elsevier.com/retrieve/pii/S0083672907000064 |access-date=2024-03-14 |publisher=Elsevier |language=en |doi=10.1016/s0083-6729(07)00006-4 |isbn=978-0-12-374113-4 |last2=Stafford |first2=Darrel W.|pmid=18374192 }}</ref> Resulting in under-carboxylation of clotting factors, meaning they are no longer capable of binding to the ] surface of blood vessels, and thus are biologically inactive.<ref>{{Cite journal |url=https://ashpublications.org/blood/article/93/6/1798/125374/Vitamin-KDependent-Biosynthesis-of |access-date=2024-03-14 |journal=Blood |doi=10.1182/blood.v93.6.1798.406k22_1798_1808 |title=Vitamin K-Dependent Biosynthesis of γ-Carboxyglutamic Acid |date=1999 |last1=Furie |first1=Bruce |last2=Bouchard |first2=Beth A. |last3=Furie |first3=Barbara C. |volume=93 |issue=6 |pages=1798–1808 |pmid=10068650 }}</ref> |
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== Metabolism == |
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The chlorophacinone is absorbed through the ] and may also be absorbed through the skin and ].<ref>{{Cite web |last=Tasheva M. |date=1995 |title=Anticoagulant rodenticides, environmental health criteria 175 |url=https://iris.who.int/bitstream/handle/10665/37676/9241571751-eng.pdf |publisher=World Health organization}}</ref> When orally ingested absorption of chlorophacinone peaks between 4 and 6 hours after initial ingesting. The compound has a half-life of approximately 10 hours. Highest concentrations of chlorophacinone are found in the liver and kidneys. Repeated oral dosing in rats suggests ] in the liver.<ref name=":0" /> After 1–4 days of repeated exposure a steady-state phase is reached. The time it takes to reach a steady-state phase suggest rapid elimination of chlorophacinone from the body.<ref name=":2" /> Anticoagulants are rapidly and principally absorbed in the intestine. The rodenticide was found to metabolized in the liver. Metabolism is mediated by ] isozymes and ring ] also appears to be an important ] step. Hydroxylation occurs on the phenyl and indandionyl rings,<ref>{{Cite journal |last1=Yu |first1=C. C. |last2=Atallah |first2=Y. H. |last3=Whitacre |first3=D. M. |date=1982-11-01 |title=Metabolism and disposition of diphacinone in rats and mice. |url=https://dmd.aspetjournals.org/content/10/6/645 |journal=Drug Metabolism and Disposition |language=en |volume=10 |issue=6 |pages=645–648 |issn=0090-9556 |pmid=6130915}}</ref> these metabolites can then further undergo conjugation with ] prior to entering the systemic circulation, with potential ]. Hepatic metabolism is generally biphasic with a rapid initial phase and more prolonged terminal phase.<ref name=":3" /> However metabolite excretion pathways of chlorophacinone still remain poorly described. The major route of elimination of chlorophacinone is through the feces (~95%) however with minor excretion (<1%) through urine and respiration. 26% of chlorophacinone is excreted within eight hours post-exposure via the bile.<ref name=":0" /> |
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== Efficacy == |
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Chlorophacinone is used as an anticoagulant rodenticide to control rodent populations in terrestrial environments. It has been proven to be very effective in efficacy studies in rats, mice and beavers.<ref>{{Cite journal |last1=Whisson |first1=Desley A. |last2=Quinn |first2=Jessica H. |last3=Collins |first3=Kellie |last4=Engilis |first4=Andrew |date=2004 |title=Developing a management strategy to reduce roof rat, Rattus rattus, impacts on open-cup nesting songbirds in California riparian forests |url=https://escholarship.org/uc/item/1wz268sx |journal=Proceedings of the Vertebrate Pest Conference |language=en |volume=21 |issue=21 |issn=0507-6773}}</ref><ref>{{Cite journal |last1=Pitt |first1=William C. |last2=Driscoll |first2=Laura C. |last3=Sugihara |first3=Robert T. |date=April 2011 |title=Efficacy of rodenticide baits for the control of three invasive rodent species in Hawaii |url=https://pubmed.ncbi.nlm.nih.gov/20552335/ |journal=Archives of Environmental Contamination and Toxicology |volume=60 |issue=3 |pages=533–542 |doi=10.1007/s00244-010-9554-x |issn=1432-0703 |pmid=20552335|bibcode=2011ArECT..60..533P }}</ref> Out of the four toxicants strychnine, zinc phosphide, chlorophacinone and diphacinone, the efficacy of chlorophacinone has been proven to be the highest in controlling mountain beaver populations. Chronic ingestion of smaller doses over time proves to be more toxic than acute ingestion of the same dose, a common trait among anticoagulant rodenticides.<ref name=":4">{{Cite journal |last1=Arjo |first1=Wendy |last2=Nolte |first2=Dale |date=2004-05-09 |title=Assessing the efficacy of registered underground baiting products for mountain beaver (Aplodontia rufa) control |url=https://digitalcommons.unl.edu/icwdm_usdanwrc/72 |journal=USDA Wildlife Services: Staff Publications|volume=23 |issue=5 |page=425 |doi=10.1016/j.cropro.2003.09.011 |bibcode=2004CrPro..23..425A }}</ref> |
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== Effects on animals == |
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Belonging to the group of first-generation anticoagulant rodenticides, chlorophacinone has similar symptoms on animals as the other chemicals in its category. Specifically, after being ingested several times by the target animal (most often a rodent), it interferes with the clotting of the blood and leads to internal bleeding, eventually causing death within 5 to 7 days. This effect is due to the rodenticide's ] of the vitamin K(1)-2,3 epoxide reductase (VKOR) enzyme which is responsible for the synthesis of vitamin K and therefore the clotting factors II, VII, IX and X, factors critical to blood clotting, lack of which eventually causes mass ] inside the animal. Although internal bleeding is the usual cause of death in this category of rodenticides, chlorophacinone has also been shown to cause additional ] or neurologic symptoms in laboratory rats, often leading to their death before significant bleeding occurs.<ref name=":1" /><ref>{{Cite web |last=Pelfrene AF |date=2001 |title=Chlorophacinone - an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/chlorophacinone}}</ref> |
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== Toxicity == |
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Chlorophacinone is classified as a highly toxic substance when administered orally, dermally, or through inhalation in mammals, falling under Toxicity Category I. It is not a dermal or eye irritant, or a dermal sensitizer (Toxicity Category IV).<ref name=":0" /> Accidental exposure incidents involving lambs have shown symptoms including ], ], and facial and cervical swelling. Post-mortem examination in two of the affected lambs have revealed that all organs had a pale appearance, notably the liver, and that the lungs were heavier than usual and were slightly brownish.<ref>{{Cite journal |last1=Piero |first1=Fabio Del |last2=Poppenga |first2=Robert H. |date=September 2006 |title=Chlorophacinone Exposure Causing an Epizootic of Acute Fatal Hemorrhage in Lambs |url=http://journals.sagepub.com/doi/10.1177/104063870601800512 |journal=Journal of Veterinary Diagnostic Investigation |language=en |volume=18 |issue=5 |pages=483–485 |doi=10.1177/104063870601800512 |pmid=17037620 |issn=1040-6387}}</ref> In four beavers exposed to 2.13 ± 0.4 mg/kg chlorophacinone, bleeding from the mouth, gasping for breath and convulsions were observed, and the beavers died within 15 days after exposure.<ref name=":4" /> Studies in rats have indicated that male rats experience more profound effects than female rats. Birds are not as sensitive to chlorophacinone as mammals, but they may still experience sublethal effects from it, such as external bleeding, internal hematoma and increased blood coagulation time. General toxic symptoms include dyspnea, lethargy, hemorrhage from the nose and urethral bleeding.<ref name=":0" /> |
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The LD<sub>50</sub> values for different species: |
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{| class="wikitable" |
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|'''Species''' |
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|'''LD<sub>50</sub> value (mg/kg)''' |
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|Male rat |
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|3.15 |
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|10.95 |
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|0.329 |
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|1.94 |
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|258 |
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|Redworm |
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|>300 |
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The SENSOR-pesticide database documented 12 human exposure cases involving chlorophacinone between 1998 and 2011. One was a moderate severity case, which involved an insulation worker being exposed to chlorophacinone dust by touching and/or inhaling it. The worker experienced shakiness, fever, and vomiting, as well as respiratory, neurological, gastrointestinal, renal and cardiovascular symptoms. Another case involved a homeowner who experienced shortness of breath and coughing after accidentally inhaling chlorophacinone. No ] assessments have been conducted on chlorophacinone since chronic exposure is not likely to occur.<ref name=":0" /> |
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== Environmental risk == |
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In order to control the population of animals such as ]s, ], ]s and ]s, chlorophacinone bait is distributed into burrow openings or on the ground just outside burrows. Although each placement is covered with grass or shingle to avoid exposing nontarget organisms and chlorophacinone is not likely to drain into soil, nontarget organisms could still be exposed to chlorophacinone by eating the bait. Predators could also eat animals poisoned with chlorophacinone, which is classified as secondary exposure, although multiple poisoned animals must be consumed to receive a ]. The anticoagulant concentration is diluted ten-fold in secondary exposure, and even more when the predator also eats non-poisoned prey.<ref name=":4" /> Small, granivorous animals that share burrows with the target animal are mainly at risk to be exposed. In a study summarized by USEPA (2004), chlorophacinone baits were used to control California ground squirrels in rangelands, and nontarget deer mice and San Joaquin pocket mice were found dead with at least 86% of the mortalities likely due to bait exposure. The risk of chlorophacinone exposure to birds is minimal, and the aquatic and terrestrial plant exposure is considered negligible.<ref name=":0" /> |
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== See also == |
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* ] |
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==References== |
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{{Reflist}} |
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{{rodenticides}} |
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