Serum and milk concentrations of several sulphonamides and their N4-acetyl metabolites following oral administration to cows

Serum and milk concentrations of sulphonamides following oral administration of three commercial sulphonamide products to dairy cows were studied. The fate of the N⁴-acetyl derivatives of the compounds was also monitored. Sulfadimidine was found to have the slowest oral absorption rate compared to sulfametoxypyridazine, sulfa-phenazole and sulfanilamide. Sulfaphenazole was least absorbed. Excretion of the different sulfonamides into the milk was by passive diffusion and was best for the least ionized sulfanilamide followed by sulfadimidine and sulfamethoxypyridazine. The most ionized sulfaphenazole was not found in milk. Sulfanilamides was found to be readily acetylated (and sulfaphenazole to a lesser degree). N⁴-acetyl-sulfanilamide seemed to be actively secreted from blood into milk in the cow.Key words: sulphonamides, farmaco kinetics, acetylation     

Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulphadiazine and their N4-acetyl and hydroxy metabolites in pigs

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N4-acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half-lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6-hydroxymethylsulphamerazine and 4-hydroxysulphadiazine were detected in plasma. The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6-hydroxymethyl and 4-hydroxy derivatives) and SDZ (4-hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimination, because their renal clearance values were higher than those of the parent drug.     

Active mammary excretion of N4-acetylated sulphanilamide

After administration of sulphanilamide to goats and cows, sulphanilamide is excreted into milk. The concentrations of sulphanilamide in ultrafiltrate of milk (M. Ultr.) and blood plasma (P. Ultr.) are equal and the ratio M. Ultr./P. Ultr. is 1.0. The pK_a of sulphanilamide is 10.4 and thus, sulphanilamide is un-ionized in both milk and blood plasma. Therefore, sulphanilamide is excreted into milk in accordance to the theory of passive diffusion of the non-protein-bound and un-ionized fraction in blood plasma (Rasmussen 1958, 1966; Miller et al. 1967). A similar ratio was expected for acetylated sulphanilamide with a pK_a of 10.3. However, the concentration of the acetylated derivative is always found higher in milk than in plasma. This might be due to formation of acetylated sulphanilamide in the mammary tissue, as demonstrated by Rasmussen & Linzell (1967) or active excretion of the compound just as in the case of N⁴-acetylated p-aminohip-puric acid (Rasmussen 1969).     

In vitro antimicrobial activity of hydroxy and N4-acetyl sulphonamide metabolites

Hydroxylated metabolites of sulphadimidine, sulphamerazine, sulphatroxazole, sulphamethoxazole, and sulphadiazine exhibited antimicrobial activity against Escherichia coli 28 PR 271 test strain ranging from 2.5 to 39.5 per cent of that of the parent drug. Trimethoprim addition potentiated the antimicrobial activity of these metabolites. N4-acetyl sulphonamide metabolites possessed no antimicrobial activity, nor did trimethoprim potentiated them.     

Pharmacokinetics, renal clearance, tissue distribution, and residue aspects of sulphadimidine and its N4-acetyl metabolite in pigs

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N4-acetylsulphadimidine (N4-SDM) concentration-time curve runs parallel to that of SDM. The percentage of N4-SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 +/- 5.4% and administered mixed with pelleted feed for 3 consecutive days it was 48.0 +/- 11.5%. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N4-SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion. After i.v. administration, 51.9% of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N4-SDM. Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N4-SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N4-SDM concentration parallelled the plasma concentrations. Negative results obtained with a semi-quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0.1 mu/g tissue.     

In vitro antimicrobial activity of hydroxy and N4‐acetyl sulphonamide metabolites

Summary

Hydroxylated metabolites of sulphadimidine, sulphamerazine, sulphatroxazole, sulphamethoxazole, and sulphadiazine exhibited antimicrobial activity against Escheria coli 28 PR 271 test strain ranging from 2.5 to 39.5 per cent of that of the parent drug. Trimethoprim addition potentiated the antimicrobial activity of these metabolites. N₄‐acetyl sulphonamide metabolites possessed no antimicrobial activity, nor did trimethoprim potentiated them.     

Pharmacokinetics of hexobarbital, sulphadimidine and chloramphencoliin neonatal and young pigs.

Half-life and apparent specific volume of distribution of hexobarbital, sulphadimidine and chloramphenicol were investigated in newborn, 1, 3, 5 and 8 weeks old pigs. Hexobarbital sleeping time and plasma concentration of hexobarbital at recovery were measured in the same age groups. The half-life of hexobarbital and chloramphenicol was long in newborn pigs but decreased fast during the first week after birth. From 1 to 8 weeks after birth the decrease was less pronounced. The half-life of sulphadimidine increased during the first 3 weeks of life, but in 1 and 3 weeks old pigs the amount of N⁴-acetylated sulphadimidine in plasma at 200 min. after the injection was higher than in the newborn pigs.The apparent specific volume of distribution of hexobarbital, sulphadimidine and chloramphenicol was changed in different ways from birth to 8 weeks of age.The hexobarbital sleeping time was very long in the newborn pigs and decreased until 3 weeks of age. The concentration of hexobarbital in plasma at recovery was unchanged from birth to 8 weeks of age.The concentration of chloramphenicol metabolites in plasma 100 min. after the injection increased very fast during the 8 weeks of observation. The concentration of N⁴-acetylated sulphadimidine in plasma at 200 min. after the injection increased from birth to 1 week of age, then it decreased.The data are stressing that the neonatal pig is a convenient model for pharmacokinetic testing of drugs used as pharmacotherapeutics in neonatal life.     

Pharmacokinetics and renal clearance of sulphadimidine,sulphamerazine and sulphadiazine and their N4‐acetyl and hydroxy metabolites in pigs

Summary

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N₄‐acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half‐lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6‐hydroxymethylsulphamerazine and 4‐hydroxysulphadiazine were detected in plasma.

The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6‐hydroxymethyl and 4‐hydroxy derivatives) and SDZ (4‐hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimentation, because their renal clearance values were higher than those of the parent drug.     

Drug plasma levels following administration of trimethoprim and sulphonamide combinations to broilers

Trimethoprim (TMP) was administered in combination with either sulphadiazine or sulphadimidine to broilers, and plasma concentrations were determined simultaneously by newly developed thin-layer and/or high-performance liquid-chromatographic procedures, which also allowed quantification of the N4-acetyl metabolites of the sulphonamides. After i.v. injection of TMP (20 mg/kg body wt) and sulphadiazine (100 mg/kg body wt), both compounds were rapidly eliminated from plasma with half-lives of 1 and 2.7 h, respectively. Apparent volumes of distribution (3.3 and 0.96 l/kg, respectively) indicated that the tissue distribution of TMP was more extensive than that of the sulphonamide. After oral administration of the same dosages, elimination appeared to be slower compared to the i.v. injection, but this was obviously related to delayed absorption. Bioavailability after oral administration was approximately 100% of sulphadiazine, but only about 60% for TMP. Oral dosing of TMP in combination with sulphadimidine yielded similar maximum plasma concentrations of both compounds to those obtained with the combination of TMP with sulphadiazine, but the plasma concentration decline of sulphadimidine appeared to be more rapid than that of sulphadiazine after oral administration. During prolonged administration of different dosages of TMP-sulphadiazine combinations via drinking water, only low plasma concentrations were attained by the recommended dosage of the combination. Up to 10-fold higher dosages were tolerated by the animals without side-effects. In view of the fact that the sensitivity of bacterial strains to TMP-sulphonamide combinations differs widely, the plasma concentrations determined in the present study during prolonged drinking-water medication with different dosages of a TMP-sulphadiazine combination can be used to select effective doses for treatment of different poultry diseases.     

Absorption from water as an alternative method for the administration of sulphonamides to rainbow trout, salmo gairdneri. The significance of the pKa value of the sulphonamides and the pH and salt content of the water.

The effect of variations in pH and salt concentration on the absorption by rainbow trout of sulphonamides from water was investigated. Two trials were carried out: 1) Absorption from fresh water of sulphanilamide (pKa 10.4) and sulphadimidine (pKa 7.4) at pH 4, 6, 8 and 10 over a period of 96 hrs., and 2) Absorption from fresh water and sea water (salinity approx. 31 ‰) of the same two sulphonamides at pH 6 and 8 over a period of 24 hrs. The degree of acetylation of the two sulphonamides in rainbow trout was investigated.     

Pharmacokinetics and renal clearance of sulfamethazine, sulfamerazine, and sulfadiazine and their N4-acetyl and hydroxy metabolites in horses

Plasma disposition, protein binding, urinary recovery, and renal clearance of sulfamethazine (SMZ), sulfamerazine (SMR), and sulfadiazine (SDZ) and their N4-acetyl and hydroxy derivatives were studied in 4 horses in a crossover trial. The plasma concentration-time curves of the metabolites paralleled those of the parent drug in the elimination phase. Sulfamethazine and SMR were extensively metabolized. In plasma and urine, the main metabolite of the 3 sulfonamides tested was the 5-hydroxypyrimidine derivative, which was highly glucuronidated. Difference in elimination half-life of SMZ, SMR, and SDZ could be related to difference in metabolism and renal clearance values. Metabolism speeds drug elimination, producing compounds with higher renal clearance values than those of the parent drug. Methyl substitution in the pyrimidine side chain increased hydroxylation of the parent drug, but prolonged the persistence of the sulfonamides studied in the body. The high concentration of N4-acetyl and hydroxy metabolites of SMZ and SMR in plasma and urine decreased the potential antibacterial activity of the parent drugs. Sulfadiazine was less metabolized, and microbiologically determined SDZ concentrations in plasma and urine were slightly lower than those measured by high-performance liquid chromatography.     

Effect of tick-borne fever on the disposition of sulphadimidine and its metabolites in plasma of goats

The effect of tick-borne fever (TBF) on the plasma disposition of sulphadimidine (SDM) and its metabolites in goats was studied. In uninfected goats, SDM was extensively metabolised mainly by hydroxylation, glucuronidation and to a minor extent by acetylation. In TBF infected goats the hydroxylation of SDM into 6-methylhydroxysulphadimidine (SCH2OH) as well as into 5-hydroxysulphadimidine (SOH) was markedly reduced (-57.6 and -63.6 per cent, respectively). An unidentified metabolite (metabolite X) was detected, which was largely glucuronidated in the uninfected goats. In the TBF infected goats the glucuronide derivatives of the X metabolite and of SOH were barely detectable. In TBF infected goats the plasma concentration of the N4-acetylated metabolite (N4-SDM) was decreased to a lesser extent (-22.1 per cent) than the hydroxy metabolites. Due to the diminished metabolism the elimination half-life of SDM was increased 1.8 times and the total sulphonamide body clearance was diminished compared with findings in the control experiments.     

Pharmacokinetics,renal clearance,tissue distribution,and residue aspects of sulphadimidine and its N4‐acetyl metabolite in pigs

Summary

Pharmacokinetics and tissue distribution experiments were conducted in pigs to which sulphadimidine (SDM) was administered intravenously, orally, and intramuscularly at a dosage of 20 mg SDM/kg. SDM was acetylated extensively, but neither hydroxy metabolites nor their derivatives could be detected in plasma, edible tissues or urine. Following i.v. and two oral routes of administration, the N₄‐acetylsulphadimidine (N₄‐SDM) concentration‐time curve runs parallel to that of SDM. The percentage of N₄‐SDM in plasma was in the range between 7 and 13.5% of the total sulphonamide concentration. The bioavailability of SDM administered in a drench was 88.9 ± 5.4 % and administered mixed with pelleted feed for 3 consecutive days it was 48.0 ± 11.5 %. The renal clearance of unbound SDM, which was urine flow related, was 1/7 of that of creatinine, indicating reabsorption of the parent drug. The unbound N₄SDM was eliminated three times faster than creatinine, indicating that tubular secretion was the predominant mechanism of excretion.

After i.v. administration, 51.9 % of the administered dose was recovered in urine within 72 h p.i., one quarter of which as SDM and three quarters as N₄‐SDM.

Tissue distribution data obtained at 26, 74, 168, and 218 h after i.m. injection revealed that the highest SDM concentration was found in plasma. The SDM concentration in muscle, liver, and kidney ranged from one third to one fifth of that in plasma. The N₄‐SDM formed a minor part of the sulphonamide content in edible tissues, in which the SDM as well as the N₄‐SDM concentration parallelled the plasma concentrations.

Negative results obtained with a semi‐quantitative bioassay method, based on monitoring of urine or plasma, revealed that the SDM concentration levels in edible tissues were in that case below 0. 1μ/g tissue.     

Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows

The effect of molecular structure on the drug disposition and protein binding in plasma and milk, the urinary recovery, and the renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy derivatives were studied in calves and cows. Sulfadiazine was highly acetylated and was slightly hydroxylated. Sulfamerazine and sulfamethazine were hydroxylated predominantly at the methyl group of the pyrimidine side chain; hydroxylation of the pyrimidine ring itself was more extensive for sulfamethazine than for sulfamerazine. At dosages between 100 and 200 mg/kg of body weight, sulfamethazine had a capacity-limited elimination pattern, which was not observed for sulfadiazine or sulfamerazine. The concentrations of the parent sulfonamide and its metabolites in plasma and milk were parallel, the latter being lower. Metabolite concentrations in milk were at least 8 times lower than those of the parent drug. Metabolism speeds drug elimination, producing compounds with renal clearance values higher than those of the parent drug. The effect on the metabolism and renal clearance of methyl substitution in the pyrimidine side chain is discussed.     

Alternative methodologies to estimate ingestion of caecotrophes in growing rabbits

This study was carried out in order to estimate caecotrophe intake in growing rabbits by three existing procedures: caecotrophes collection after collar fitting, urinary purine derivatives (PD) excretion and microbial ¹⁵N-lysine incorporation. In a first experiment sixteen New Zealand White male rabbits were divided in three groups receiving the same diet, but supplemented with ¹⁵NH₄Cl in the first group (T₁: 6 rabbits). The second group (T₂: 6 rabbits) was also fed the labelled diet but only during the last ten days of the fattening period when animals were fitted a neck collar to prevent caecotrophy. The third group (T₃: 4 animals) received the basal diet and was used as control. In two additional trials the daily contribution to urinary excretion of endogenous purine compounds (469 ± 50.8 μmol/W^0.75) and creatinine excretion (807 ± 127.6 μmol/W^0.75) were determined. The highest estimation of microbial nitrogen recycling was obtained by the urinary PD method (0.79 ± 0.096 g/d), whereas caecotrophes collection and ¹⁵N-lysine incorporation methods showed similar values (0.49 ± 0.049 and 0.45 ± 0.015 g/d, respectively). Our results seem to indicate an overestimation of microbial nitrogen recycling in growing rabbits by PD methodology, while neck collar fitting procedure gave similar results, although more variable than microbial ¹⁵N-lysine incorporation.     

Effect of pantothenic acid on disposition kinetics and tissue residues of sulphadimidine in chickens

Sulphadimidine was administered to chickens via the intracrop route to determine plasma concentrations of the unchanged sulphonamide and its acetylated derivatives, kinetic disposition, tissue residues and acetylation. The sulphadimidine was given alone (group 1) at a dose of 200 mg kg-1 bodyweight. Pantothenic acid was given via the intracrop route at a dose of 100 mg kg-1 bodyweight one hour before (group 2) and six hours after (group 3) sulphadimidine administration (200 mg kg-1 bodyweight intracrop). The highest plasma concentrations of sulphadimidine in groups 1, 2 and 3 were reached in 1.73, 1.62 and 1.71 hours, respectively, following intracrop administration. In birds of groups 1, 2 and 3 no sulphadimidine was detected at 72, 24 and 48 hours, respectively, following its administration. Estimation of sulphadimidine in most of the body tissues revealed that all tissues examined had lower concentrations than plasma. In chickens given pantothenic acid (groups 2 and 3) before and after sulphadimidine administration, an increase in the concentration of N4 acetylated derivatives of sulphadimidine was observed compared with birds given sulphadimidine alone (group 1).     

Some pharmacokinetic aspects of four sulphonamides and trimethoprim, and their therapeutic efficacy in experimental Escherichia coli infection in poultry

Pharmacokinetic studies in broilers and layers of different sulphonamides indicate a good absorption and a long elimination half-life (of sulphaquinoxaline, sulphadimidine and to a lesser degree sulphadiazine) resulting in high plasma concentrations during drinking water medication in the recommended therapeutic doses. In contrast drinking water medication with high concentrations of trimethoprim (up to 1,320 mg/liter) resulted in a maximal mean plasma concentration of 1.2 micrograms/ml. Very good therapeutic effects were demonstrated in broilers experimentally infected with a sulphonamide-susceptible E. coli strain when treated with sulphaquinoxaline (200 mg/liter), sulphadimidine sodium (2 gram/liter), sulphachloropyridazine 30 per cent (1 gram/liter) and to a lesser degree sulphadiazine sodium (250 mg/liter). Synergism was demonstrated between trimethoprim and sulphadiazine (1:5). The combination of trimethoprim with sulphaquinoxaline (1:3) did not induce better therapeutic effects than sulphaquinoxaline in proportional doses. However, significant synergism was demonstrated between trimethoprim and both sulphonamides in treatment of experimental infection with sulphonamide-resistant E. coli. No signs resembling sulphonamide intoxication were observed during these studies.     

Pharmacokinetics and urinary excretion of sulphadimidine in buffalo calves

Pharmacokinetics and urinary excretion of sulphadimidine (SDI) were determined in buffalo calves following single oral administration (150 mg/kg). The plasma levels of free sulphadimidine were above minimum effective therapeutic concentration (> 40 micrograms/ml) between 4 and 12 h and the N4-acetylated form of the drug was in the range of 7.2-19.3%. Kinetic evaluation of plasma levels was performed using a two-compartment open model. The absorption and elimination half-lives of SDI were 3.01 and 11.94 h, respectively. Based on this study, an optimal dosage regimen of sulphadimidine in buffalo calves would be 100 mg/kg, followed by 50 mg/kg at 12 h intervals. Sulphadimidine was mainly excreted in the urine as free amine. The percentage of N4-acetyl sulphadimidine in urine was comparatively higher than in plasma.     

Antibacterial drugs used against mastitis in cattle by the systemic route

The veterinarian in clinical practice is often confronted with cases of mastitis that require systemic antibacterial treatment in addition to local treatment. This paper reviews the suitability of drugs available in New Zealand, taking into account their anti-staphylococcal activity, routes of administration, and their ability to attain and maintain therapeutic levels in the udder following systemic administration. The drugs considered include the more common penicillins, aminoglycosides and macrolides; oxytetracyline, chloramphenicol, trimethoprim, and several sulphonamides.

The success of systemic therapy against mastitis depends to a large extent on the concentration of antibacterial drug achieved at foci of infection. Passage of drugs across the blood-milk barrier takes place by passive diffusion, and the factors influencing this diffusion are discussed.

Whe mastitis is associated with sensitive organisms, penicillin is recommended, although, as with all other antibacterials discussed, the dose used must be higher than normal. For penicillin, doses of the order of 16,500 iu/kg are recommended.

The intramuscular injection of oxytetracycline will not produce therapeutic levels in milk but, after intravenous injection of high doses (10 mg/kg), this antibiotic is likely to maintain therapeutic levels in milk over a 24-hour period.

As a first choice for the systemic treatment of mastitis, either tylosin or erythromycin is recommended. At a dose rate of 12.5 mg/kg, either will maintain for 24 hours milk levels in excess of the average MICs for staphylococci.

Of the sulphonamides, sulphanilamide and sulphadimidine produce the highest milk levels. After intravenous administration at a dose rate of 200 mg/kg, sulphadimidine will maintain therapeutic levels in milk for 12 hours.

Although trimethoprim has a very short half-life in cattle which limits its usefulness, it readily enters the milk and a combination of trimethoprim (as a suspension) with sulphadiazine, at a dose rate of 48 mg/kg, might be expected to maintain therapeutic levels in the milk for 12 hours.

It is concluded that dihydrostreptomycin, neomycin, chloramphenicol, and the combination sulphadoxine/trimethoprim, are not suitable for the systemic treatment of bovine mastitis.     

Dose dependent disposition of sulphadimidine and of its N4-acetyl and hydroxy metabolites in plasma and milk of dairy cows

The disposition of sulphadimidine (SDM) and of its N4-acetyl (N4-SDM) and two hydroxy metabolites, 6-hydroxymethyl-(SCH2OH) and 5-hydroxyasulphadimidine (SOH), was studied in plasma and milk of dairy cows following intramuscular or intravenous administration of sulphadimididine-33.3% at doses of 10, 45, 50, and 100 mg/kg. The main metabolite in plasma as well as in milk was SCH2OH. The metabolite percentages, the final plasma elimination half-lives, and the time of peak SDM concentrations in milk are presented for different dosages. The concentrations of SDM and its metabolites in milk ran parallel to those in plasma beyond 4 hours p.i. The metabolite concentrations in plasma and milk were lower than those of the parent SDM. Sulphate and glucuronide metabolites could not be detected in milk. At high doses (45 mg/kg or more) and SDM plasma concentrations exceeding 20 micrograms/ml, a capacity limited metabolism of SDM to SCH2OH was noticed, viz. a steady state concentration of SCH2OH and a biphasic elimination pattern for SDM and SCH2OH in plasma and milk. The mean ultrafiltrate ratios of the milk to plasma concentrations with respect to SDM, SCH2OH, SOH, and N4-SDM were: 0.69, 0.22, 020, and 0.63, respectively. The total amount of SDM and its metabolites recovered from the milk after milking twice daily over the whole experimental time was less than 2% of the applied dose. A bioassay method allowed of detecting qualitatively SDM concentrations exceeding 0.2 micrograms/ml in plasma or milk. Withholding times for edible tissues and milk are suggested.