WHO Acute Hazard classification of pesticides: Not listed

Mechanism of action of Sarolaner

• Sarolaner (the active ingredient of SIMPARICA) and other isoxazolines with insecticidal and tickicidal efficacy are non-competitive GABA (gamma-aminobutyric acid) receptor antagonists, much more selective for GABA receptors in insects or ticks, than for those in mammals, including humans. They bind to chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Affected parasites are paralyzed and die.
• This mechanism exists not only in insects but also in mammals and other vertebrates. However the binding affinity of sarolaner to GABA receptors of invertebrates is much higher than to GABA receptors in vertebrates. For this reason it is significantly less toxic to mammals than to insects and other pests.

Acute Toxicity and Tolerance of Sarolaner

• LD50 acute, rats, p.o. 783 mg/kg
• LD50 acute, rats, dermal >2020 mg/kg.
• In repeat-dose toxicity studies in rats, the target organs are the adrenal glands, liver and ovaries.
• NOAEL (No observed adverse effect level) in rats: 0.233 mg/kg/day in the 30 days study; 0.25 mg/kg/day in the 90 day study. In rats, gross enlargement of the adrenal glands at 22.33 mg/kg/day in males and female was related to higher adrenal gland weights and microscopic hypertrophy of zona fasciculata cells of the adrenal cortex. At 2.233 mg/kg/day effects on the liver were observed (dose dependent vacuolation in females accompanied by decreased triglyceride levels in blood). Moreover, vacuolation in the adrenal gland was observed in males and adrenal gland weights were increased in females. Also (dose dependent) histopathological changes were observed in the ovary.
• In dogs neurological effects were noted at doses of 20 mg/kg (convulsions, tremors and ataxia) and 12 mg/kg (tremors, ataxia). Signs appeared to occur primarily in the first 24 hours after dosing and resolved without treatment. No effects on the nervous system were observed in any animal at 4 mg/kg.
• Prenatal developmental toxicity studies have not shown any teratogenic effects, but studies of the effects on reproduction were not provided. Sarolaner is not genotoxic and no carcinogenicity studies were carried out.
• Sarolaner is well tolerated in Collies with a deficient multidrug-resistance-protein 1 (MDR1 -/-) following single oral administration at 5 times the recommended dose. No treatment-related clinical signs were observed. Such dogs are particularly susceptible to treatment with macrocyclic lactones (e.g. ivermectin, milbemycin oxime, moxidectin, selamectin, etc.)

Toxic Symptoms, Side Effects, Adverse Drug Reactions (ADRs) caused by Sarolaner

• In general dogs tolerate very well sarolaner at the therapeutic dose range (2 to 4 mg/kg).
• Simparica may cause abnormal neurologic signs such as tremors, unsteadiness, and/or seizures. Simparica has not been evaluated in dogs that are pregnant, breeding or lactating.
• According to EMEA, Simparica (the product that contains sarolaner) was found to be well tolerated by animals treated with the recommended treatment dose of 2–4 mg sarolaner/kg bw. However, at overdoses (3X or more the recommended dose) neurological effects (tremor, ataxia, convulsions) were observed.
• In a margin of safety study, Simparica was administered orally to 8 week old Beagle puppies at doses of 0, 1, 3, and 5 times the maximum exposure dose of 4 mg/kg at 28 day intervals for 10 doses. No adverse effects were observed at the maximum exposure dose of 4 mg/kg. In the overdose groups, transient and self-limiting neurological signs were observed in some animals: mild tremors at 3 times the maximum exposure dose and convulsions at 5 times the maximum exposure dose. All dogs recovered without treatment.
• A potential administration error in dogs is administration to small dogs of tablets approved for larger animals.
• In laboratory safety studies, no interactions were observed when sarolaner was co-administered with milbemycin oxime, moxidectin and pyrantel pamoate. (In these studies efficacy was not investigated).
• In September 2018 the FDA of the USA has alerted pet owners and veterinarians about potential neurological adverse events following the use of products containing isoxazolines in dogs. In August 2021 The FDA has extended this alert to cats. Some treated animals have experienced adverse events such as muscle tremors, ataxia (lack of voluntary coordination of muscle movements), and seizures. This regards all products containing isoxazolines. Most treated animals will not show such adverse drug reactions, but some may be affected.

Antidote and Treatment of Sarolaner Intoxication

• There is no antidote for sarolaner poisoning.
  
• Treatment consists in preventing further exposure together with supportive and symptomatic measures.
• After accidental ingestion stomach lavage as well as administration of active charcoal administration and laxatives may be advisable.

Pharmacokinetics of Sarolaner

• Sarolaner administered orally to dogs is quickly absorbed into blood. Absorption to blood does not depend on the prandial state of the patient, i.e. there is no difference in the absorption when administered to fed or to fasted animals.
• Bioavailability was high at more than 85%. Plasma protein binding was determined in vitro and calculated at ≥99.9%.
• A distribution study determined that 14C-Sarolaner-related residues were widely distributed to the tissues. The half-life was comparable for the intravenous and oral routes at 12 and 11 days, respectively.
• The depletion from tissues was consistent with the plasma half-life. The primary route of elimination is biliary excretion of the parent molecule, with minor contributions from metabolic clearance.
• Being highly bound to plasma proteins, sarolaner might compete with other highly bound substances such as non-steroidal anti-inflammatory drugs (NSAIDs) and the cumarin derivative warfarin.

Environmental Toxicity of Sarolaner

• Little has been published yet regarding the environmental toxicity of sarolaner. Its use in dogs as recommended is unlikely to pose a risk for the environment, and for this reason no environmental studies have been carried out for the approval of its use on dogs.
• Based on its mode of action it must be assumed that sarolaner is highly toxic to both aquatic and terrestrial arthropods (insects, ticks, spiders, crustaceans, etc.).

Additional information

Click here for a list and overview of all safety summaries of antiparasitic active ingredients in this site.

• Sarolaner belongs to the chemical class of the isoxazolines.
• Sarolaner is so far not used in livestock.
• Sarolaner is so far not used in human medicines.
  
• Sarolaner is so far not used in crop pesticides.
• Sarolaneris so far not used in public and domestic hygiene as a biocide.
• Click here for General safety of antiparasitics for domestic animals.
• Click here for General safety of antiparasitics for humans.
• Click here for General safety of antiparasitics for the environment.
• Click here for technical and commercial information on sarolaner.