Vertebrate Pesticide Toxicology Manual (Poisons)

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2.7 Warfarin

Chemical Name: 3-(-acetonylbenzyl)-4-hydroxycoumarin.

Synonyms: Warfarin.

Warfarin, like pindone, is one of the earliest first-generation anticoagulant rodenticides

2.7.1 Physical and chemical properties

The empirical formula for warfarin is C19H16O4 and the molecular weight is 308.3. It is a colourless, odourless, and tasteless crystalline powder with a melting point of 161ºC. It is insoluble in water and benzene, freely soluble in alkaline solution, readily soluble in acetone, and only moderately soluble in alcohols.

2.7.2 Historical development and use

Warfarin baits are registered in New Zealand for rodent control, but bromadiolone, brodifacoum, and flocoumafen are often preferred by pest managers because of their greater potency. Warfarin is a first-generation anticoagulant that has been used in a range of rodent baits since it was first introduced in 1947.

Cereal pig-baits containing warfarin are available from the Animal Control Products factory in Wanganui.

As warfarin is a first-generation anticoagulant, for most animals the baits will need to be ingested regularly over several days before any of the symptoms of poisoning will occur.

2.7.3 Fate in the environment

There are no published data on warfarin degradation. However, significant contamination of soil and water following the use of bait stations is extremely unlikely. Minor contamination is likely around the bait station, which should not be a major risk to non-target species. Degradation by soil micro-organisms and slow dispersal of warfarin in the soil is probable: this is based upon data on the degradation of similar anticoagulant toxicants.


2.7.4 Toxicology and pathology

Onset of signs and pathology

As for all anticoagulants, the onset of symptoms will depend on the dose, nature, and amount of bait consumed.

Rats

Warfarin baits administering 1 mg/kg will kill rats in 5–8 days. Rats can withstand single doses of 50 mg/kg, but are unable to survive doses of 1 mg/kg bodyweight when that dose is ingested for 5 successive days. In general the symptoms of poisoning do not appear suddenly, and will culminate in death within 5–7 days of the initial ingestion of a lethal dose.

Pigs

Approximately 3 days after poisoning, some pigs will become lame, depressed, and lethargic. Food consumption decreases and blood is commonly observed in faeces. There is a great deal of individual variation in the time it takes for pigs to die from warfarin poisoning, with some pigs dying before or soon after they have shown the initial symptoms of poisoning and others living up to 31 days, progressively weakening over time.

Mode of action

Warfarin, like the other anticoagulants, inhibits the synthesis of vitamin K-dependent clotting factors. In addition, warfarin is reported to induce capillary damage. Two different metabolites are thought to be responsible for these effects: 4 hydroxycoumarin inhibits the formulation of prothrombin and reduces the clotting power of the blood, whereas there is some evidence that, at sufficient dosage, benzalacetone produces capillary damage that exacerbates bleeding.


Pathology and regulatory toxicology

Animals may be subjected to a hypovolemic crisis secondary to massive haemorrhage into body cavities, subcutaneous tissues, and the alimentary, respiratory, and urinary tracts in cases where large doses of the toxin have been ingested. Animals that receive a lower dose of the toxin may show signs of lethargy, anaemia, anorexia, bloody faeces, and abdominal pain. In pigs, extensive haemorrhages into the stomach and the small and large intestine are the most common signs of anticoagulant pathology, with skeletal muscle, peritoneum, and weight-bearing joints common sites of haemorrhage.

There are limited regulatory toxicology studies on warfarin and no data relating to potential mutagenic effects. While all anticoagulant rodenticides are likely to be embryotoxic if ingestion occurs at a sufficiently high dose, warfarin is unique in this class of compounds and was found to be both embryotoxic and teratogenic when administered to rats (WHO 1995), causing internal hydrocephalus and anomalies of skeletal ossification. In humans undergoing continuous drug treatment with warfarin, defects have in the past been classified as warfarin embryopathy and include both skeletal and non-skeletal abnormalities. No cases of embryopathy from anticoagulants in their use as rodenticides have been reported.

Fate in animals
Absorption, metabolism, and excretion

Warfarin is readily hydroxylated by rat microsomal enzymes to at least eight metabolites, including 6-,8- and especially 7-hydroxywarfarin (Sutcliffe et al. 1987). It is not persistent, and is readily excreted with an elimination half-life of about 18 hours in male rats and 28 hours in female rats (Pyrola 1968). The half-life in rat liver is reported to be 7–10 days for warfarin, which contrasts with half-lives exceeding 100 days for second-generation anticoagulants (Thijssen 1995) (see Tables 10 and 11).


Species variation in response to warfarin

The toxicity of warfarin varies according to species and whether exposure was a single or multiple dose (Table 22). For example, the single dose LD50 is 50–100 mg/kg in rats (species unspecified) versus 1 mg/kg for 5 days (Osweiler et al. 1985).

Table 22: Acute oral toxicity (LD50mg/kg) of warfarin (Osweiler et al. 1985)

Species Single dose (mg/kg) Repeated dose (mg/kg)

Pig 3 0.5

Dog 50 5

Rat (unspecified) 50–100 1

Cat 50–100 1

Values for the acute oral LD50 of warfarin for Norway rats vary between 1.5 and 3.75 mg/kg (Hone & Mulligan 1982). The strain and sex of the test animals and the carrier used in the administration probably affected the results obtained.
Aquatic toxicology

There are no published data available for warfarin.

2.7.5 Diagnosis and treatment of poisoning

As for brodificoum, see Section 2.1.5 (pp. 57–60).

2.7.6 Non-target effects


Although less potent than 1080 or brodifacoum, warfarin still has the potential to cause primary poisoning of non-target species. Secondary poisoning is relatively uncommon (Osweiler et al. 1985; Prakash 1988).


    If warfarin baits are used for control of pest species, it is important that the baits are not positioned where livestock may eat them.

2.7.7 Summary

Advantages

Disadvantages

No licence required

Not as potent as second-generation anticoagulants or non-anticoagulant poisons such as cholecalciferol and 1080

Effective for rodent control

Antidote




Less persistent than brodifacoum






  • Warfarin is a first-generation anticoagulant.

  • In order for a lethal dose to be ingested, the target species needs to consume either one large single dose or a small dose for several days in a row.
  • Because warfarin has a slow mode of action, bait shyness is not readily induced.

  • It is not persistent when compared to brodifacoum, but is considerably less potent than second-generation anticoagulants.

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