Avermectins belong to the family of macrocyclic lactones and are the major drugs used as in-feed treatments to kill sea lice. The first avermectin used was ivermectin at doses close to the therapeutic level and was not submitted for legal approval for use on fish by its manufacturer. Ivermectin was toxic to some fish, causing sedation and central nervous system depression due to the drug's ability to cross the blood–brain barrier. Emamectin benzoate, which is the active agent in the formulation SLICE, has been used since 1999 and has a greater safety margin on fish. It is administered at 50 µg/kg/day for 7 days and is effective for two months, killing both chalimus and mobile stages. Withdrawal times vary with jurisdiction from 68 days in Canada to 175 degree days in Norway. Avermectins act by opening glutamate-gated chloride channels in arthropod neuromuscular tissues, causing hyperpolarization and flaccid paralysis leading to death. Resistance has been noted in "Chalimus rogercresseyi" in Chile and "L. salmonis" on North Atlantic fish farms. The resistance is likely due to prolonged use of the drug leading to up-regulation of P-glycoprotein, similar to what has been seen in nematode resistance to macrocyclic lactones.