Doramectin labelled with tritium in the 5-position was administered as a single dose to Sprague-Dawley rats (2 males given 5 mg/kg bw in propylene glycol:glycerol by gavage), a beagle dog (1 female given 3.5 mg/kg bw in sesame oil by gavage) and cattle (5 males given 0.2 mg/kg bw subcutaneously). /The following metabolites were identified in/... the liver and feces from each species and the fat of cattle... /unchanged doramectin, 3"-O-desmethyl doramectin, 24-hydroxymethyl doramectin, and 24-hydroxymethyl-3"-O-desmethyl doramectin./
The products of doramectin metabolism were similar in all species investigated /rats, dogs, pigs, cattle/. The metabolites were more polar than doramectin and were the result of O-demethylation in the distal saccharide ring, of hydroxylation of the 24-methyl group and a combination of both of these biotransformations.
Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
/LABORATORY ANIMALS: Acute Exposure/ Doramectin was applied to normal and abraded skin of 3 New Zealand white rabbits (0.5 g under an occlusive patch) for 24 hours. Slight erythema was observed 24 and 48 hours post-dose at 1 of 3 intact sites and 2 of 3 abraded sites. There was no edema at any site and all sites appeared normal 72 hours post-dose.
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of CD-1 mice (10/sex/dose) were administered doramectin (purity 94.1%) in the diet for 43 days. Target doses were 0, 10, 20, 40, or 60 mg/kg bw/day on days 1 to 14; 0, 10, 20, 80 or 100 mg/kg bw/day on days 15 to 28; and 0, 100, 200, 400 or 600 mg/kg bw/day on days 29 to 43. Toxic signs included lethargy, hunched posture and tremors at 400 and 600 mg/kg bw/day, and hunched and ungroomed appearance in some mice at 100 and 200 mg/kg bw/day. A number of animals given 400 and 600 mg/kg bw/day were sacrificed moribund and the remaining mice in these groups were killed on day 33. There were no effects on body weight or food consumption. Relative liver weights were slightly higher in most treated groups but the changes were minor and not dose-related. Clinical laboratory parameters and pathological examinations were not carried out.
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of CD-1 mice (10/sex/group) were fed doramectin (purity 94.1%) in the diet for 92 days. Target doses were 0, 100, 200 or 300 mg/kg bw/day. Actual doramectin intake was 83-121, 154-191 or 221-322 mg/kg bw/day. Tremors, hunched posture, unkempt appearance and lethargy were observed at the mid- and high-dose groups and resulted in death or moribund sacrifice of 9 mice at 300 mg/kg bw/day and 3 mice at 200 mg/kg bw/day. The remaining animals in these two groups were killed on day 12 or 19, respectively. Body-weight gain was depressed in association with reduced food consumption at 200 mg/kg bw/day and above. Serum creatinine and BUN were slightly increased at 100 mg/kg bw/day with no effects at higher doses, presumably due to early culling of mice in these groups. Hematological parameters were unaffected. All treated groups had increased liver weights and hypertrophy of centrilobular hepatocytes, with multinucleate non-proliferative liver cells at 100 mg/kg bw/day only. Dead and moribund animals showed lymphocyte lysis in lymphoid organs, cellular depletion of bone marrow and necrosis of the adrenal cortex which may have resulted from stress and weight loss.
In the first study, 10 dairy Holstein cows were treated with a pour-on formulation of doramectin at a dose of 0.58 mg/kg bw and were retreated with the same dose 56 days later. ... Samples of milk were collected for 49 days and 10 days, respectively, after the first and second treatments. Samples were collected twice daily until day 7, and once daily on days 10, 13, 16, 19, 22, 25, 28, 32, 36, 40 and 49. On retreatment, samples were taken twice daily until day 7 and once at day 10. ... The concentrations of doramectin residue in milk increased to a maximum mean value of 22 mg/kg at 72 hr after treatment. Mean concentrations of doramectin residues decreased to below the limit of quantitation (3 mg/kg) at 384 hr (16 days). After retreatment, concentrations of doramectin residues increased gradually to a maximum mean value of 12 mg/kg at 48 hr after dosing; and decreased to <4 mg/kg at 240 hr (10 days) after dosing. The milk/fat analyses were conducted 1, 4, and 10 days after dosing. Mean concentrations of doramectin residues in the milk fat at these time points were 171 mg/kg, 501 mg/kg and 114 mg/kg, respectively. Concentration factors for doramectin residues in milk fat were 29.6, 32.2 and 24.7, respectively.
In the second study, 10 cows were treated with doramectin by topical application of a pour-on formulation at a dose of 0.58 mg/kg and were re-treated with the same dose 56 days later. Samples of milk were collected twice daily. Concentrations of doramectin in milk increased to a maximum mean value of 9 mg/kg at 45 hr after treatment and decreased to below the LOQ by 237 hr (10 days) after treatment. After re-treatment on day 56, concentrations of residues increased to a mean maximum value of 8 mg/kg after 93 hr and decreased to less than the LOQ after 237 hr (10 days). Mean concentrations of doramectin residues in the milk fat at 1, 4, and 10 days were 91 mg/kg, 142 mg/kg and 55 mg/kg, respectively. Concentration factors for doramectin residues in milk fat versus milk were 14.2, 20.9 and 14.1, respectively.
The third study determined the residue depletion profile of doramectin following the subcutaneous administration of doramectin formulation at 0.23 mg/kg bw in lactating cattle, followed by retreatment at the same dose 56 days later. ... Doramectin concentrations in milk increased gradually to a maximum mean value of 45 mg/kg at 67 hr. Subsequently, doramectin residues gradually declined, with mean residues below LOQ at 523 hr (22 days). After re-treatment, doramectin residues increased to a maximum mean value of 53 mg/kg at 56 hr. Residue concentrations then decreased to a mean value of 25 mg/kg at 237 hr (10 days) after re-treatment. Residues resulting from treatment by injection were consistently higher at any given timepoint than were those resulting from treatment with the pour-on formulation. Milk fat analyses were conducted using samples collected at the morning milking on days 1, day 4 and day 10 after treatment. Mean concentrations of doramectin residues in milk fat at these time-points were 557 mg/kg, 1036 mg/kg and 354 mg/kg, respectively. Milk fat concentration factors were 24, 24.2 and 23.4, respectively.
Self-licking behavior in cattle has recently been identified as a determinant of the kinetic disposition of topically-administered ivermectin. /The present study documents/ the occurrence and extent of transfer between cattle of three topically-administered endectocides, as a consequence of allo-licking. Four groups of two Holstein cows each received one pour-on formulation of doramectin, ivermectin, or moxidectin, or no treatment. The cows were then kept together in a paddock. Systemic exposure to each topically-administered endectocide was observed in at least five of six non-treated cattle. Plasma and fecal drug concentration profiles in non-treated animals were highly variable between animals and within an animal, and sometimes attained those observed in treated animals. Drug exchanges were quantified by measuring plasma and fecal clearances after simultaneous i.v. administration of the three drugs as a cocktail. Plasma clearances were 185 + or - 43, 347 + or - 77 and 636 + or - 130 ml/kg/day, fecal clearances representing 75 + or - 26, 28 + or - 13, and 39 + or - 30% of the plasma clearance for doramectin, ivermectin and moxidectin, respectively. The amount of drug ingested by non-treated cattle attained 1.3-21.3% (doramectin), 1.3-16.1% (ivermectin), 2.4-10.6% (moxidectin) of a pour-on dose (500 ug/kg). The total amount of drug ingested by all non-treated cattle represented 29% (doramectin), 19% (ivermectin), and 8.6% (moxidectin) of the total amount of each drug poured on the backs of treated animals. The cumulative amounts of endectocide ingested by each non-treated cow ranged from 1.3 to 27.4% of a pour-on dose. Oral bioavailability after drug ingestion due to allo-licking was 13.5 + or - 9.4, 17.5 + or - 3.5 and 26.1+ or - 11.1% for doramectin, ivermectin and moxidectin, respectively. The extent of drug exchange demonstrated here raises concerns for drug efficacy and safety, emergence of drug resistance, presence of unexpectedly high residue levels in treated and/or untreated animals and high environmental burdens.
来源:Hazardous Substances Data Bank (HSDB)
安全信息
危险品标志:
N,T,Xi
安全说明:
S26,S33,S36/37,S45,S60,S61
危险类别码:
R25
WGK Germany:
3
海关编码:
29419090
危险品运输编号:
UN2811 - class 6.1 - PG 3 - EHS - Toxic solids, organic, n.o.s., HI: all