Page 569 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

536 SECTION | VI Insecticides

VetBooks.ir observed. At 10 mg/kg body wt/day, body weight gains and abnormal neurological responses) in animals of both
sexes. One animal at 2 mg/kg body wt/day was humanely
and food consumption were reduced in animals of either
euthanized because of poor condition related to treatment.
sex. Some animals showed hyperactivity. The NOAEL
was calculated to be 5 mg/kg body wt/day. Primary der- The NOAEL was identified to be 0.2 mg/kg body wt/day.
mal irritation in rabbits was examined in two studies. In another study, fipronil was administered in the diet
Fipronil was slightly irritating when moistened with corn at doses of 0, 0.075, 0.3, 1 or 3 mg/kg body wt/day for
oil before application, but was not irritating when moist- 1 year. At 1 mg/kg body wt/day, clinical signs of neurotox-
ened with water. Fipronil was slightly irritating in two icity (whole body twitching and extensor rigidity of limbs)
studies of primary ocular irritation in rabbits. It did not were noted in females. There were no effects on T3 or
sensitize the skin of guinea pigs when tested by the T4 levels. The NOAEL was identified to be 0.3 mg/kg
Buehler method, but was a weak sensitizer in guinea pigs body wt/day.
when tested by the Magnusson-Kligman method (WHO, A neurotoxicity study was performed in female dogs
1998 99). This product was reported to be contraindi- (WHO, 1998 99). In this study, dogs received fipronil
cated in rabbits because deaths occurred when a spray for- in capsules at doses of 0 (one animal) or 20 mg/kg body
mulation of fipronil was used. Extra-label use in rabbits wt/day (four animals) until the appearance of neurotoxic
could produce anorexia, lethargy, convulsions and death. signs in each animal, after which they were allowed
In rabbits, fipronil produces serious adverse reactions, to recover for 28 days. Severe neurotoxic signs were
suggesting that this species is unusually sensitive to fipro- observed at a dose of 20 mg/kg body wt/day during the
nil. Young rabbits are particularly more sensitive than treatment phase. Most animals appeared to recover,
adults. Frontline has been considered to be improper for although one had exaggerated reflex responses and was
rabbits. excitable at the end of the recovery period.
One reproductive toxicity study was performed in rab- Poisoning cases of fipronil occur in dogs and cats due
bits (WHO, 1998 99). Rabbits treated with fipronil by to accidental ingestion/licking of Frontline product. There
gavage at doses of 0, 0.1, 0.2, 0.5 or 1 mg/kg body wt/day is some indication that dogs are more severely affected
during gestation days 6 19 showed no developmental than cats. Application of Frontline Spot-On, Certifect or
toxicity, but there were some signs of maternal toxicity Parastar Plus to dogs and cats can cause skin irritation
(decreased body weight gain, decreased food consumption and/or hair loss at the site of application. Dermal hyper-
and reduced efficiency of food use at all doses). The sensitivity reactions may also occur. In a series of clinical
NOAEL for developmental toxicity was identified to be studies, dogs topically treated with fipronil-containing
1 mg/kg body wt/day. In a number of experimental stud- ectoparasiticide products (Frontline Spot-On, Certifect or
ies, fipronil has been found to be a reproductive and Parastar Plus) did not show any skin reactions (Jennings
developmental neurotoxicant, and effects appeared to be et al., 2002; Nichols et al., 2014; Case et al., 2016).
due to alterations in either the GABAergic system or via Common clinical signs of fipronil toxicosis are of CNS
endocrine disruption (Ohi et al., 2004; Stehr et al., 2006; hyperexcitability, including tremors, convulsions, seizures
Lassiter et al., 2009; Sidiropoulou et al., 2011; Roques and death (Grant et al., 1998; Hainzl et al., 1998;
et al., 2012; Udo et al., 2014; Khan et al., 2015). Kamijima and Casida, 2000).

Dogs and Cats Domestic Animals
Several subacute and chronic toxicity studies of fipronil In a subacute study, buffalo calves orally exposed with
have been performed in dogs (WHO, 1998 99). In a sub- fipronil (0.5 mg/kg body wt/day) produced toxic signs
acute toxicity study, fipronil was administered in gelatin including salivation, lacrimation, dullness, depression,
capsules to dogs for 13 weeks at doses of 0, 0.5, 2 or decreased body weight gain, muscle weakness, alopecia
10 mg/kg body wt/day. Inappetence and decreased body and sunken eyes. Fipronil-exposed animals recovered
weight gain and food consumption were noted in females within 2 weeks after discontinuation of treatment
at 2 and 10 mg/kg body wt/day. The NOAEL was (Gill and Dumka, 2013).
reported to be 0.5 mg/kg body wt/day.
In a chronic study, fipronil was administered to dogs Birds and Fish
in gelatin capsules for 1 year at doses of 0, 0.2, 2 or
5 mg/kg body wt/day. At 2 mg/kg body wt/day and On an acute and subchronic level, fipronil is practically
higher, there were clinical signs of neurotoxicity (convul- nontoxic to slightly toxic in waterfowl with an acute oral
sions, twitching, tremors, ataxia, unsteady gait, rigidity of LC 50 of .2000 mg/kg and a 5-day dietary LC 50 of
limbs, nervous behavior, hyper- or hypoactivity, vocaliza- .5000 mg/kg in mallard ducks. The oral LC 50 for bob-
tion, nodding, aggression, resistance to dosing, inappetence white quail is 11.3 mg/kg, and the LC 50 for 5-day dietary