WORLD HEALTH ORGANIZATION FOOD AND AGRICULTURE ORGANIZATION ORGANISATION MONDIALE DE LA SANTE ORGANISATION POUR L'ALIMENTATION ET L'AGRICULTURE VBC/DS/85.62 ORIGINAL: ENGLISH DATA SHEETS ON PESTICIDES No. 62 CHLOROPHACINONE It must be noted that the issue of a Data Sheet for a particular pesticide does not imply endorsement of the pesticide by WHO or FAO for any particular use, or exclude its use for other purposes not stated. While the information provided is believed to be accurate according to data available at the time when the sheet was compiled, neither WHO nor FAO are responsible for any errors or omissions, or any consequences therefrom. The issue of this document does Ce document ne constitue pas une not constitute formal publication. Il ne doit faire publication. It should not be l'objet d'aucun compte rendu ou reviewed, abstracted or quoted résumé ni d'aucune citation sans without the agreement of the l'autorisation de l'Organisation Food and Agriculture des Nations Unies pour Organization of the United l'Alimentation et l'Agriculture Nations or of the World Health ou de l'Organisation Mondiale de Organization. la Santé. CLASSIFICATION: Primary use: Rodenticide Secondary use: Chemical group: Indandione derivative 1. GENERAL INFORMATION 1.1 COMMON NAME: Chlorophacinone (ISO, BSI and JMAF) 1.1.1 Identity; IUPAC: 2-(2-(4-chlorophenyl)-2-phenylacetyl)indan-1, 3-dione CAS: 2-(2-(4-chlorophenyl)-phenylacetyl)-1H-indene-1, 3(2H)-dione CAS Reg. No.: 3691-35-8 Molecular formula: C23H15ClO3 Molecular weight: 374.8 Structural formula: 1.1.2 Synonyms: AFNORR; CaidR; chlorofacinon; chlorfacinon; chlorophacinone; DeltaR; DratR; LiphadioneR; LM 91R: MicrozulR; MuriolR; QuickR; RamucideR; RanacR; RatometR; RaviacR; RozolR; TopitoxR. 1.2 SYNOPSIS: Chlorophacinone is a chlorinated, diphenyl indane derivative; an anti-coagulant and metabolic inhibitor which is highly toxic to rodents but of only slight toxicity to humans and other non-target organisms. It is compatible with a wide spectrum of bait carriers and has no repellent action. 1.3 SELECTED PROPERTIES 1.3.1 Physical characteristics Chlorophacinone is a white crystalline solid. It has a melting point of 140°C, it is non-corrosive. 1.3.2 Solubility Chlorophacinone is sparingly soluble in water, but soluble in organic solvents. 1.3.3 Stability Chlorophacinone is described as stable and resistant to weathering effects. 1.3.4 Vapour pressure Negligible at 20°C. 1.4 AGRICULTURE, HORTICULTURE AND FORESTRY 1.4.1 Common formulations Chlorophacinone is available as a bait, 50-250 mg a.i./kg and in oil solution, 2.5 g a.i./L. 1.4.2 Pests controlled Presently used against mice, moles, muskrats, rats, vampire bats, and voles - in controlled access areas and under field conditions. 1.4.3 Use pattern Chlorophacinone is applied wherever the rodents have access to the bait. It may be replenished as it is consumed. A tracking powder is recommended in areas where rodents travel. It does not usually require more than one feeding for a kill. The oil solution may be used to impregnate or coat any desirable bait. Prevent food contamination. 1.4.4 Unintended effects Chlorophacinone could be hazardous to other small mammals and birds if used indiscriminately. Persons with bleeding problems and children should not come in contact. 1.5 PUBLIC HEALTH USE As in 1.4, for control of nuisance and disease vector rodent pests. 1.6 HOUSEHOLD USE As in 1.4, for control of nuisance and disease vector rodent pests. 2. TOXICOLOGY AND RISKS 2.1 TOXICOLOGY - MAMMALS 2.1.1 Absorption route Chlorophacinone is primarily absorbed from the gastrointestinal tract; dermal absorption may also occur. 2.1.2 Mode of action Chlorophacinone is an anticoagulant agent; it uncouples oxidative phosphorylation depressing hepatic synthesis of prothrombin and clotting factors VII, IX and X and, it causes direct damage to capillary permeability. The ultimate effect is widespread internal haemorrhage. In rodents, indandlones also cause neurologic and cardiopulmonary injuries which often lead to death before haemorrhage occurs. 2.1.3 Excretion products No published information available. 2.1.4 Toxicity, single dose A single dose of a 50 mg/kg bait kills Rattus norvegicus from the fifth day. Oral LD50: Rat 20.5 mg/kg bw; technical material Rabbit 50.0 mg/kg bw; technical material Dermal LD50: Rabbit 200.0 mg/kg bw; technical material A solution of 5 mg in 2 ml of liquid paraffin applied to 100 cm2 of shaved skin on rabbits caused only a slight reduction of prothrombin rating. 2.1.5 Toxicity, repeated doses No published information available. Cumulation of compound No published information available. 2.1.6 Dietary studies No published information available. 2.1.7 Supplementary studies of toxicity No published information available. 2.1.8 Modification of toxicity No published information available. 2.2 TOXICOLOGY - MAN 2.2.1 Absorption Chlorophacinone is primarily absorbed from the gastrointestinal tract, it may also be absorbed through the intact skin and, inhalation of residual bait dust may also occur. 2.2.2 Dangerous doses No published information available. It is assumed that, because of low bait concentrations and the delayed nature of the toxic effect, it would require the ingestion of over one kilogram of the bait to produce toxic effects. Persons with "bleeding problems" should avoid contact. 2.2.3 Observations of occupationally exposed workers No published information available. 2.2.4 Observations on exposure of the general population No published information available. 2.2.5 Observations of volunteers Human volunteers tolerated a single dose of 20 mg a.i. without ill-effects. 2.2.6 Reported mishaps No published information available. In reports of cases involving similar poisons the compounds were either taken deliberately, were absorbed chronically out of neglect of basic hygiene or were ingested when rodent baits were inadvertently used as food. 2.3 TOXICITY TO NON-MAMMALIAN SPECIES 2.3.1 Fish No published information available. 2.3.2 Birds Chlorophacinone is of low toxicity to birds. Administration of 15 daily doses of 2.25 mg to grey partridges produced no ill- effects. Oral LD50: Wild Birds 430 mg/kg bw; technical material Ducks 100 mg/kg bw; technical material 3. FOR REGULATORY AUTHORITIES - RECOMMENDATION ON REGULATION OF COMPOUND 3.1 RECOMMENDED RESTRICTIONS ON AVAILABILITY (For definition of categories see introduction.) All formulations, categories 4 and 5. 3.2 TRANSPORT AND STORAGE Formulations in category 4 - Should be transported in clearly labelled, rigid and leakproof containers out of reach of children, away from food and drink. Storage should be under lock and key and secure from access by children and other unauthorized persons. Formulations in category 5 - Should be transported and stored in clearly labelled, leakproof containers out of reach of children, away from food and drink. 3.3 HANDLING Formulations in category 4 - Protective clothing should be used by all handling the compound. Adequate washing facilities should be available at all times during handling and they should be close to the site of handling. Eating, drinking and smoking should be prohibited during handling and before washing of hands and face after handling. Baits of chlorophacinone should be removed and the area thoroughly cleaned up after purpose has been fulfilled. Formulations in category 5 - No facilities other than those needed for the handling of any chemical are required. Baits of chlorophacinone should be removed and the area thoroughly cleaned up after purpose has been fulfilled. 3.4 DISPOSAL AND/OR DECONTAMINATION OF CONTAINERS All formulations - Containers should not be decontaminated and should not be used for any other purpose. Containers should be burned or should be crushed and buried below topsoil. Care must be taken to avoid subsequent contamination of water sources. 3.5 SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS Formulations in categories 4 and 5 - A pre-employment examination is essential to exclude from contact all persons with blood and vascular disorders predisposing them to haemorrhaging. A periodic medical examination should include tests of blood clotting time, prothrombin levels, capillary fragility and a record of evidence of blood in the excreta. 3.6 ADDITIONAL REGULATIONS IF DISTRIBUTED BY AIRCRAFT NOT APPLICABLE 3.7 LABELLING Formulations in category 5 - Minimum cautionary statement - "CAUTION". This formulation contains chlorophacinone, it may be poisonous if swallowed. Keep this material out of reach of children and well away from food, animal feed and food utensils. Avoid skin contact, wear impermeable gloves when handling and wash immediately after handling the compound. In case of contact, immediately remove contaminated clothing and wash the skin thoroughly with soap and water; for eyes, flush with water for 15 minutes. If poisoning occurs, call a physician. Vitamin K is a specific antidote. 3.8 RESIDUES IN FOOD Maximum residue levels have been recommended by the Joint FAO/WHO Meeting on Pesticide Residues. 4. PREVENTION OF POISONING IN MAN AND EMERGENCY AID 4.1 PRECAUTIONS IN USE 4.1.1 General Chlorophacinone is a rodenticide; an anticoagulant and a metabolic inhibitor. It depresses hepatic synthesis of factors essential to blood clotting and causes increased capillary permeability which ultimately lead to internal haemorrhage. Indandiones should be considered more toxic than warfarin though their health hazard to humans may be considerably diminished by their low concentration in most formulations and their delayed action. Chlorophacinone is primarily absorbed from the gastrointestinal tract; to a limited extent through intact skin; and, inhalation of bait dust may also occur. 4.1.2 Manufacture and formulation - TLV No information. Closed systems and forced ventilation may be required to reduce, as much as possible, the exposure of workers to the chemical. 4.1.3 Mixers and applicators When opening a container and when mixing, protective impermeable boots, clean overalls, impermeable gloves and a respirator should be worn. Mixing, if not mechanical, should always be carried out with a paddle of appropriate length. Avoid contact with mouth and eyes. Before eating, drinking or smoking, hands and other exposed skin should be thoroughly washed with alkaline soap. 4.1.4 Other associated workers All persons exposed to the concentrate and associated with its formulation should observe the precautions described above in 4.1.3. 4.1.5 Other populations likely to be affected With good agricultural practice, subject to 4.2 below, other populations are not likely to be exposed to hazardous amounts of the compound. 4.2 ENTRY OF PERSONS INTO TREATED AREAS Chlorophacinone is relatively persistent, all exposed baits should be clearly marked and identified as a poison. Under these conditions, unprotected adult persons may enter the treated area immediately after application without being exposed to a health hazard. 4.3 SAFE DISPOSAL OF CONTAINERS AND SPILLAGE Residues in containers should be emptied in a dilute form into a deep pit taking care to avoid contamination of ground waters. Decontamination of containers in order to use them for other purposes should not be permitted. Spillage should be removed as much as possible and as soon as possible into a deep dry pit and the residue washed away with large quantities of water. The residue and containers may also be burned in a well-ventilated location. 4.4 EMERGENCY AID 4.4.1 Early symptoms of poisoning The signs and symptoms of acute poisoning from a large dose are not likely to be immediately apparent. When the body's reserves of prothrombin have been diminished, after two or three days following a single large dose or after a few weeks of repeated ingestion of small doses, bleeding gums, pallor, swelling and tenderness of the joints, haematomata, blood in the urine and faeces, and abdominal pains may occur. Paralysis, haemorrhagic shock and death may follow in cases of severe poisoning. Cardiopulmonary and neurologic symptoms seen in rats have not been reported in human victims. 4.4.2 Treatment before a person is seen by a physician Due to the delayed appearance of symptoms, it is unlikely that specific symptoms will be seen directly following exposure. If the compound has been swallowed, vomiting should be induced immediately if the person is conscious; call a physician immediately and transport the victim to hospital as soon as possible. 5. FOR MEDICAL AND LABORATORY PERSONNEL 5.1 MEDICAL DIAGNOSIS AND TREATMENT IN CASES OF POISONING 5.1.1. General information Chlorophacinone is a rodenticide; an anticoagulant and a metabolic inhibitor; and, it may specifically inhibit Vitamin K1-epoxidase activity. It depresses hepatic synthesis of factors essential to normal blood clotting and causes increased fragility and permeability of capillaries leading to widespread internal haemorrhage. Chlorophacinone is absorbed primarily from the gastrointestinal tract and to a limited extent through the intact skin. It is highly toxic to rodents but it is considered to be slightly toxic to humans, in most formulations. 5.1.2 Symptoms and signs The victims of small ingested doses and even those of substantial, hypoprothrombinemia inducing doses are usually asymptomatic,. The onset of clinical signs of poisoning may be delayed several days after exposure to a single large dose or after a few weeks of repeated ingestion of small doses. The signs of poisoning are epistascis and bleeding gums; pallor and sometimes petechial rash; massive ecchymoses and/or haematomata (especially of the articulating joints); blood in urine and faeces; occasionally paralysis due to cerebral haemorrhage; and, haemorrhagic shock and death. Cardiopulmonary and neurologic signs and symptoms, common in rat poisonings, have not been reported in human cases. 5.1.3 Laboratory The principle diagnostic test in a demonstration of markedly reduced prothrombin activity in blood plasma, as measured by the method of Quick or one of its modifications. The test should be repeated at least twice daily until a normal prothrombin time is established. Also, the blood clotting time and the bleeding time should be obtained. Blood is often demonstrable in the excreta. Secondary anaemia (hypochromic and microcytic) may be marked. 5.1.4 Treatment If small amounts of the compound have been ingested by either an adult or a child and the victim is asymptomatic, treatment is probably unnecessary. If there is uncertainty about the dose or the general health of the victim, Vitamin K1 may be given orally as a prophylactic treatment. Observe the patient for 4-5 days. If the dose is known to be large or the victim is showing signs of poisoning, induce vomiting with Syrup of Ipecac or perform a gastric lavage within 2-3 hours of ingestion. Follow with activated charcoal treatment to limit absorption of any toxicant remaining in the gastrointestinal tract. Vitamin K1 is a specific antidote, 5- 10 mg by subcutaneous or intramuscular injection may be repeated if necessary. Only if the victim is bleeding severely or otherwise in serious distress should the drug be given intravenously at a rate no more than 1 mg/min. On subsequent days Vitamin K1 treatment may be continued, if necessary. The usual precautions in Vitamin K1 therapy should be followed. Small transfusions of fresh whole blood may be necessary or an immediate and temporary source of prothrombin and erythrocytes. Vitamin C may be a useful adjunct to Vitamin K1 therapy, at 100 mg several times a day as necessary. Neither Vitamins K3 nor K4 are effective antidotes in cases of Indandione poisoning. Following the establishment of control of haemorrhage and the repair of the coagulation defect, iron replacement therapy should be initiated to correct the secondary anaemia. In severe incidences it may also be necessary to aspirate the haematomas after normal blood clotting has been restored. 5.1.5 Prognosis If the acute toxic effect is survived, the chances of complete recovery are very good provided that subdural haemorrhages or vascular lesions in other tissues do not: produce secondary effects. 5.1.6 References of previously reported cases No information available. 5.2 SURVEILLANCE TESTS Blood clotting time and bleeding time could be monitored in chronically exposed individuals. Also, vigilance for blood in the excreta and peripheral signs of capillary fragility is appropriate. The blood levels of active Vitamin K1 relative to Vitamin K1-expoxide or the level of Vitamin K1 epoxidase would also prove useful to assess overexposure or the progress of therapy. 5.3 LABORATORY METHODS 5.3.1 Detection and assay of compound Bullard, R. W. et al. (1975) J. Agric. Food Chem., 23(1), 72. Davis, R. S. (1977), Bull. OEPP, 7(2), 477. Grant, R. G. & Pike, R. K. (1979), J. Assoc. Off. Anal. Chem, 62(5), 1001. Kawano, Y. & Chang, W. (1980), J. Assoc. Off. Anal. Chem, 63(5), 996. Reynolds, R. (1980), Proc. Annu. Meet. Am. Assoc. Vet. Lab.; 23, 187. Vigh, G. et al. (1981), J. Chromatogr., 214(3), 335.