Browsing by Author "Prinsloo, Marlien"

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    The residue kinetics and safety of R-salbutamol in ruminants
    (Stellenbosch : Stellenbosch University, 2019-04) Prinsloo, Marlien; Hoffman, Louwrens C.; Stellenbosch University. Faculty of Agrisciences. Dept. of Animal Sciences.
    ENGLISH ABSTRACT: With an increased demand to supply food to an ever-increasing world population the application of new technologies to improve animal production efficiency has become a global priority. A balance must be found however between the production benefit of these technologies, animal welfare and human safety. The purpose of the two studies undertaken was to determine the target animal tolerance of R-salbutamol when included in feed, the remaining residues in liver, kidney, muscle and fat following various withdrawal periods, and the withdrawal period at which animal tissue will be safe for human consumption. To determine the withdrawal period, the residues detected in animal tissue must be compared to the Acceptable Daily Intake (ADI) of R-salbutamol in humans. As no extensive toxicological evaluation has ever been done for R-salbutamol, a complete evaluation of available toxicological data was performed. Repeat dose studies, carcinogenicity, genotoxicity, reproductive, foetal and acute toxicity data were evaluated to determine the ADI. No carcinogenicity, genotoxicity or reproductive toxicity were noted for R-salbutamol. Long-term effects were observed with a No Adverse Effect Level (NOAEL) of 12 mg/kg BWt. Foetal toxicity (teratology) were noted at high inclusion levels in rabbits (cranioschisis at 50 mg salbutamol/kg BWt) with a NOAEL of 10.75 mg/kg derived from a rat teratology study. The Acute Reference Dose (ARfD), derived from human studies, was however the lowest safe level with a NOAEL (also referred to as the point of departure (POD)) of 1mg R-salbutamol/kg BWt, due to the possible acute effects of R-salbutamol ingestion at higher inclusion levels. An ARfD of 3 μg/kg BWt were calculated and used as the upper limit of the ADI, which was determined to be 0 - 3 μg/kg BWt in humans. The lamb feedlot study included 13 lambs; one lamb being slaughtered at the start of the trial as control. The remaining 12 lambs were treated with 21 mg R-salbutamol per day (0.5 mg/kg BWt) for 28 days. R-salbutamol was withdrawn from the feed 7 hours prior to slaughter for 6 of the lambs and withdrawn for 24 hours from the feed for the remaining 6 lambs. Liver, kidney, muscle and fat samples were collected at slaughter and analysed for parent and total salbutamol (parent + metabolites) residues. Heart rate, rectal temperature and respiratory rate were measured before the start of the medicated period (study day -1) and again on day 28 of the medicated period. Heart rate did not differ between day -1 and 28, but respiratory rate and rectal temperature were both higher at day 28 compared to day -1 (P < 0.05). The increase in rectal temperature was not clinically significant as it remained within normal parameters. The increase in respiratory rate in 7 of the 12 lambs was attributed to lower respiratory tract infection. Parent salbutamol residues in lambs were the highest in the liver (± 89% of residues detected) at 7 hours withdrawal, followed by the kidney (± 7%), fat (± 2.5%) and muscle (± 1%). The residue concentrations at 24 hours after withdrawal were less than 50% of the levels detected at 7 hours following withdrawal. Metabolism of R-salbutamol is rapid following absorption due to high pre-systemic metabolism as indicated by the high level of metabolites detected following hydrolysis of tissue samples with β-glucoronidase. At 7 hours after withdrawal, 44% of the total residues were present as parent salbutamol in the liver and 39% at 24 hours after withdrawal. In the kidney 28% and 30% of parent salbutamol were detected at 7 hours and 24 hours, respectively as a percentage of total salbutamol. Muscle had 47% parent salbutamol as a percentage of total salbutamol at 7 hours after withdrawal. The percentage reduced to 17% after 24 hours withdrawal. In fat, 11% of total salbutamol were present as parent salbutamol at 7 hours and 14% 24 hours after withdrawal. The theoretical maximum daily intake of salbutamol for humans calculated from the lamb residue data is less than 10% (16.88 μg/day) of the acceptable daily intake (ADI) (180 μg/kg BWt in adult human). Animal tissue from feedlot lambs fed R-salbutamol, according to label recommendations, with zero withdrawal in feed, will provide adequate consumer protection. In a similar study performed in beef cattle one group of four cattle received non-medicated feed as the negative control group. Three groups of six cattle each received 150 mg R-salbutamol/head/day (0.42 mg/kg BWt) in feed for 44 days. One animal from the control group was slaughtered on study day 3. The three medicated groups were slaughtered on <12-, 24- and 48-hours following withdrawal of R-salbutamol from feed respectively together with one each of the control group. The control animals were included to show that there were no residues occurring naturally within the test herd. Liver, kidney, muscle and fat samples were collected and analysed for salbutamol residues. No residues were detected for total salbutamol (LOQ = 3 μg/kg) in any of the tissues. No visual adverse events were observed in the study animals and R-salbutamol was well tolerated in feedlot cattle. From the data in this study MRL for R-salbutamol is therefore suggested to be set for liver at 300 μg/kg, muscle at 6.5 μg/kg, kidney at 40 μg/kg and fat at 13 μg/kg. At these levels the daily intake of residue will still be below 20% of the ADI. Further investigation into intravenous and oral pharmacokinetics of R-salbutamol in both lambs and cattle will be beneficial to better understand the absorption, distribution, metabolism and excretion of R-salbutamol in feedlot lambs and cattle.