Toxicological Properties of Closantel

Abstract

The acute, subacute and chronic toxicity studies in laboratory animals showed that closantel is a well tolerated substance. At multiples of the clinical dose, overdosing might result in central nervous system effects and death. Repeated oral dosing was without effects up to 40 mg/kg in rats and dogs except for focal swelling of the epididymis in male rats at 40 mg/kg due to formation of spermatic granulomas. In sheep repeated dosing at 10 and 40 mg/kg orally and at 5 and 20 mg/kg intramuscularly every four weeks during 40 weeks demonstrated an acceptable safety margin in this target species. Reproduction studies including a three-generation study in rats showed that fertility was not affected except slightly in male rats at 40 mg/kg whereas an embryotoxic or teratogenic potential in rats and rabbits was absent. Peri- and postnatal parameters in rats were not affected. In target animals, reproduction was extensively studied in bulls, rams and ewes showing no risk of closantel for reproduction parameters. A mutagenic potential was found to be absent in a Salmonella Ames test, a sex-linked recessive lethal test in Drosophila melanogaster and a dominant lethal test in male and female mice. In 400 mice and 400 rats closantel was shown not to be carcinogenic. Tolerance studies in sheep and cattle demonstrated that oral and parenteral clinical doses were very well tolerated and devoid of serious side-effects.

Closantel toxicity in a pregnant ewe at mid gestation: the pathological evaluation of the ewe and lamb nine months later

“…The therapeutic dose of closantel is 10 mg/kg. In studies carried out by Janssen Pharmaceuticals, the first fatalities following oral overdose are reported at 70 mg/kg when tested on healthy sheep (Van Cauteren and others 1985). This is in contrast to reported toxicities in the field that have documented adverse effects including death at 30 mg/kg (Gill and others 1999) and more recent reports of blindness at levels as low as 10–14 mg/kg (Crilly and others 2014).…”

“…However, the effects of closantel toxicity on mid gestation pregnant ewes and, furthermore, the lamb in utero have not been previously reported. Previous embryo toxicity studies carried out in ewes included the delivery of 20 or 40 mg/kg once on day 11, 17 or 23 of gestation (Van Cauteren and others 1985). These ewes were observed to have equal distribution of repeat breedings and perinatal death between treated and untreated control groups.…”

Clastogenic Effects of the Fasciolicides Closantel and Nitroxynil on Mice Somatic and Germ Cells

“…Both drugs induced a high percentage of chromosme aberrations in spermatocyte cells, that reflect the male reproductive toxicity specially of Closantel (Mantovani 1992). Toxicity studies for Van Cauteren 1985, showed that Closantel at repeated oral dose was without effects up to 40 mg kg Ϫ1 b.wt. in rats except for focal swelling of epididymis in male due to formation of spermatic granuolomas.…”

“…Toxicity studies in laboratory animals showed that Closantel has a non-mutagenic potential in Salmonella Ames test, and a dominant lethal test in male and female mice. Tolerance studies in sheep and cattle demonstrated that oral and parental clinical doses were very well tolerated and devoid of serious side-effects (Van cauteren et al 1985).…”

Diagnostic différentiel des troubles à expression nerveuse dans l’espèce bovine en Europe occidentale

“…Elles se rencontrent lors de surdosage, d'un mauvais usage des médicaments, d'utilisation de préparations non autorisées ou d'une sensibilité particulière liée à la race ou l'âge. Les principaux principes actifs dont l'usage nécessite une attention particulière sont les suivants : les quinolones (148), les nitrofuranes qui sont interdits d'utilisation (2,35,137), les sulfamidés (62), la lincomycine qui peut induire une acétonémie (11,121), les aminosides (11,39), mais aussi certains antiparasitaires, antiprotozoaires ou anthelminthiques comme les dérivés d'avermectines et de milbémycines tels que la moxidectine (observations cliniques non publiées), les salicylanilidés pouvant entraîner de la cécité (11,147), l'amprolium (146), le lévamisole/tétramisole (47) et les organophosphorés.…”