Approval Date: March 4, 1994
I. General Information:
NADA Number: 141-025
Syntex Animal Health
Division of Syntex Agribusiness, Inc.
3401 Hillview Avenue
Palo Alto, CA 94304
Established Name: laidlomycin propionate potassium
Trade Name: Cattlyst®
Marketing status: OTC
Effect of Action:
Approval of this original NADA provides for the use of laidlomycin propionate potassium (hereafter referred to as laidlomycin propionate) in cattle fed in confinement for slaughter for increased rate of weight gain and improved feed efficiency.
II. Indications for Use:
For increased rate of weight gain and improved feed efficiency of cattle fed in confinement for slaughter.
III. Dosage Form, Route Of Administration, and Recommended Dosage:
Laidlomycin propionate promix, 50 g of laidlomycin propionate potassium per pound. Laidlomycin propionate premix should be admixed into feed and fed at a dietary concentration of 5 to 10 g of laidlomycin propionate/ton of feed (90% dry matter basis) to provide not less than 30 nor more than 150 mg/animal/day.
Summary of pivotal dose-response efficacy trials:
Data were pooled from five replicated, well-controlled studies involving 764 animals and which were conducted in various geographic areas of the United States. Steers were used in all five studies, and heifers were used in one of the studies. Duration of the trials ranged from 126 to 170 days. The cattle were fed a variety of diets which ranged in energy content from 2.60 to 3.15 Meal ME/kg of dry matter. Laidlomycin propionate was administered in the feed and fed at dietary concentrations that ranged between 0 and 10 g/ton of feed, 90% dry matter basis. An unweighted, combined-trials statistical analysis Coy analysis of variance) was performed on data from the five trials and included the doses common to all five trials (0, 5, 7.5 and 10 g/ton). The ANOVA model contained terms for trial, concentration of laidlomycin propionate, trial by concentration interactions .and weight block nested within trial.
Laidlomycin propionate improved rate of gain and feed efficiency in both steers and heifers. Average daily gain was maximized by laidlomycin propionate at 5 g/ton while feed efficiency was improved by incremental increases in laidlomycin propionate through 10 g/ton, regardless of diet fed. These conclusions were drawn from pooling five trials (Virginia, Colorado, Illinois, Kansas, and Texas). Because the Kansas trial did not contain laidlomycin propionate at 2.5 g/ton, the analysis was done using laidlomycin propionate concentrations of O, 5, 7.5, and 10 g/ton. In the trials where 2.5 g/ton was used, consistent improvements in performance were not obtained when laidlomycin propionate was used at 2.5 g/ton.
COMBINED-TRIAL PERFORMANCE OF CATTLE FED DIETS CONTAINING LAIDLOMYCIN PROPIONATE
|Variables||Laidlomycin propionate (g/ton, 90% DMB) - 0||Laidlomycin propionate (g/ton, 90% DMB) - 5||Laidlomycin propionate (g/ton, 90% DMB) - 7.5||Laidlomycin propionate (g/ton, 90% DMB) - 10|
|Daily gain, kg/d||1.15||1.25||1.22||1.25|
|Kg feed DM/kg gain||9.05||8.39||8.44||8.13|
Individual pivotal efficacy trials:
Study IAS 1109-379(3):
One hundred twenty Angus and Angus x Hereford steers were used in a 126-d feeding trial to study the influence of laidlomycin propionate at 0, 2.5, 5, 7.5 and 10 g/ton on feedlot performance. This trial was conducted by Dr. Joseph P. Fontenot, Virginia Polytechnic Institute and State University, Blacksburg. Cattle were fed a high-roughage diet based on corn silage. One steer exhibited chronically poor performance throughout the study. No adverse reactions to laidlomycin propionate were observed.
PERFORMANCE OF CATTLE FED LAIDLOMYCIN PROPIONIATE, IAS 1109-379(3)
|Variables||Laidlomycin propionate (g/ton, 90% DMB) - 0||Laidlomycin propionate (g/ton, 90% DMB) - 2.5||Laidlomycin propionate (g/ton, 90% DMB) - 5||Laidlomycin propionate (g/ton, 90% DMB) - 7.5||Laidlomycin propionate (g/ton, 90% DMB) - 10|
|No. of replicates||3||3||3||3||3|
|Total no. of steers||24||24||23||24||24|
|Initial weight, kg||338.9||339.5||337.7||341.7||339.8|
|Kg feed DM/kg gain||10.88||11.19||9.83||9.77||9.55|
Study IAS 1109-379(4):
One hundred forty Angus and Angus x Hereford steers were used in a 126-d feeding trial to study the influence of laidlomycin propionate at 0, 2.5, 5, 7.5 and 10 g/ton on feedlot performance. The trial was conducted by Dr. Larry L. Berger, University of Illinois, Urbana. Cattle were fed a high-energy diet based on high-moisture corn and corn silage. One steer died on study day 50 with a diagnosis of tracheitis. No adverse reactions to laidlomycin propionate were observed.
PERFORMANCE OF CATTLE FED LAIDLOMYCIN PROPIONATE, IAS 1109-379(4)
|Variables||Laidlomycin propionate (g/ton, 90% DMB) - 0||Laidlomycin propionate (g/ton, 90% DMB) - 2.5||Laidlomycin propionate (g/ton, 90% DMB) - 5||Laidlomycin propionate (g/ton, 90% DMB) - 7.5||Laidlomycin propionate (g/ton, 90% DMB) - 10|
|No. of replicates||4||4||4||4||4|
|Total no. of steers||28||28||27||28||28|
|Initial weight, kg||338.3||342.4||339.6||339.3||340.7|
|Final weight, kg||521.0||514.8||531.8||525.7||533.4|
|Kg feed DM/kg gain||6.32||6.37||6.09||6.06||5.83|
Study IAS 1109-379(6):
Dr. Mary I. Wray, Horton Feedlot and Research Center, Wellington, Colorado conducted a 132-d feeding trial with two hundred crossbred steers fed laidlomycin propionate at 0, 2.5, 5, 7.5 and 10 g/ton. Cattle were fed a high-energy diet based on cracked corn. No adverse reactions to laidlomycin propionate were observed.
PERFORMANCE OF CATTLE FED LAIDLOMYCIN PROPIONATE, IAS 1109-379(6)
Laidlomycin propionate (g/ton, 90% DMB) ____________________________________________________ Variables 0 2.5 5 7.5 10 No. of replicates 4 4 4 4 4 Total no. of steers 40 40 40 40 40 Initial weight, kg 375.7 371.6 374.1 372.8 375.9 Final weight, kg 528.4 527.4 534.0 527.9 542.1 Gain, kg/d 1.16 1.18 1.21 1.18 1.26 Kg feed DM/kg gain 8.06 7.71 7.81 7.92 7.50
Study IAS 1109-379(7):
A dose-response trial was conducted by Dr. Rodney L. Preston, Texas Tech University, Lubbock. One hundred sixty crossbred steers were used in a 170d feeding trial with laidlomycin propionate fed at O, 2.5, 5, 7.5 and 10 g/ton. Steers were fed a high-energy diet based on steam-flaked sorghum grain. Two animals which exhibited chronically poor performance were removed. No adverse reactions to laidlomycin propionate were observed.
PERFORMANCE OF CATTLE FED LAIDLOMYCIN PROPIONATE, IAS 1109-379(7)
Laidlomycin propionate (g/ton, 90% DMB) ______________________________________________________ Variables 0 2.5 5 7.5 10 No. of replicates 4 4 4 4 4 Total no. of steers 31 32 31 32 32 Initial weight, kg 305.4 303.1 305.1 302.7 304.7 Final weight, kg 457.9 466.4 465.9 466.2 465.4 Gain, kg/d .90 .96 .95 .96 .95 Kg feed DM/kg gain 9.20 8.76 8.77 8.75 8.82
Study IAS 1109-379(5):
A 126-d feeding trial was conducted by Dr. Jack G. Riley, Kansas State University, Manhattan, to confirm the efficacy of laidlomycin propionate in both steers and heifers. Seventy-two crossbred steers and 72 heifers were fed an 85 % concentrate diet based on rolled sorghum grain. No adverse reactions to laidlomycin propionate were observed.
PERFORMANCE OF CATTLE FED LAIDLOMYCIN PROPIONATE, IAS 1109-379(5)
Laidlomycin propionate (g/ton, 90% DMB) ____________________________________________ Variables 0 5 7.5 10 No. of replicates 6 6 6 6 Total no. of animals 36 36 36 36 Initial weight, kg 333.5 333.9 333.2 333.9 Final weight, kg 489.3 507.1 499.3 507.7 Gain, kg/d 1.24 1.37 1.32 1.38 Kg feed DM/kg gain 9.93 8.92 9.06 8.55
V. Animal Safety
Pivotal Animal Safety Studies:
Study 168-B0-87 - Tolerance in cattle.
Three steers and 3 heifers averaging approximately 270 kg were used in a study conducted by Dr. D.E. Bidlack, Syntex. Two steers and two heifers were given seven daily oral doses of 1500 mg of laidlomycin propionate by gelatin capsule. One steer and one heifer were given capsules containing vehicle (soybean millrun) only. The 1500 mg doses of laidlomycin propionate per head daily averaged 5.55 mg/kg/day and were approximately 16-fold greater than the predicted daily doses would have been for these cattle if they had been fed this diet containing laidlomycin propionate at 10 g/ton of feed, 90% dry matter basis. Observations and laboratory measurements were made for 2 weeks after administration of the last dose. All cattle received complete necropsies which included pathologic examination of all organ systems and body cavities. Tissues were examined microscopically.
Severe clinical signs of laidlomycin propionate toxicosis, which included anorexia, profuse watery diarrhea, severe weight loss, reduced rumen activity (atony), bradycardia, abnormal eating behavior (pica), dullness and/or listlessness, were observed in all four laidlomycin propionate-treated calves. Heifers were more severely affected than the steers, and one heifer died 4 days after receiving the last dose of laidlomycin propionate. Anorexia was observed in all four laidlomycin propionate-treated calves within 12 hours of the first dose. Profuse watery diarrhea was present within 24 hours of the first dose. Bradycardia was evident after the third day of dosing. Rumen atony essentially paralleled anorexia in the treated cattle.
Increases in erythrocyte counts, hemoglobin, and hematocrit noted in the laidlomycin propionate-treated calves during the latter half of the dosing period and continuing for the first week of the postdosing period were consistent with hemoconcentration and dehydration. Likewise, decreased alkaline phosphatase and sorbitol dehydrogenase values and increased creatinine and blood urea nitrogen concentrations during the same time period were associated secondarily with anorexia and diarrhea. Gross pathologic changes present in heifers and related to laidlomycin propionate toxicosis included increased intestinal fluid contents and tan areas in the myocardium. Histopathologic changes in the myocardium of heifers were characterized by edema, myocardial fiber degeneration and vacuolation, necrosis, leukocyte infiltration, and fibrosis. Cardiopathy was considered to be the cause of death of the heifer which died. Less severe changes, characterized by pale staining myocardial fibers and myocardial edema, were present in the hearts of steers.
Study 161-B0-87 - Chronic toxicity in Cattle.
A study using laidlomycin propionate at dietary concentrations of 0, 10, 30 and 50 g/ton, 90% dry matter basis was conducted by Dr. R. Spencer Swingle, University of Arizona, Tucson. Mixed beef-breed steers and heifers with mean initial body weights of 141 and 137 kg, respectively, were assigned randomly to treatments. Cattle were housed seven per pen with three pens per sex per treatment assigned to the control and 10 g of laidlomycin propionate/ton treatments and two pens per sex per treatment assigned to the 30 g of laidlomycin propionate and 50 g of laidlomycin propionate/ton treatments. Feed consumption of each pen was monitored throughout the trial. Individual body weights were obtained at the initiation of the study, at approximately 28-day intervals throughout the study and at termination of the 265-day trial. Hematology and clinical chemistry determinations were made on blood samples taken from four preselected animals from each pen at the same intervals. Animals were observed daily and a record of clinical condition was maintained on a weekly basis. At termination of the study, necropsy examinations were conducted on three steers and three heifers preselected from each treatment. Tissue samples from the six animals fed the control diet and the six animals fed laidlomycin propionate at 50 g/ton plus all altered tissues from all study animals were examined microscopically.
Dry matter intake was decreased for cattle that received dietary laidlomycin propionate at concentrations of 30 and 50 g/ton. Average daily gain among treatments essentially paralleled the rate of dry matter intake, with the lowest rate of dry matter intake and ADG occurring in the steers that received 50 g of laidlomycin propionate/ton. No statistically significant differences in feed efficiency among treatments was observed. An increased incidence of loose feces was present in heifers that were fed laidlomycin propionate at a dietary concentration of 50 g/ton. There were no differences among treatments in hematologic or clinical chemistry observations or in the gross or microscopic pathology observations.
VI. Human Food Safety:
a. Toxicity Tests:
Study 8-R-82 - Subchronic toxicity in rats.
Five groups, each composed of 20 male and 20 female rats, were administered by gavage doses of 0 (vehicle), 1, 2, 4, or 8 mg laidlomycin propionate/kg of body weight once daily for three months. The daily dose was adjusted to the weekly group-average body weight for males and for females. Laidlomycin propionate was dissolved daily in 90% propylene glycol just before use. Clinical observations, body weights, and food intakes were recorded weekly. Ophthalmologic examinations were conducted during the predose period and during the last month of treatment. Urine samples were collected during the last week of treatment. Blood samples for hematology and clinical chemistry evaluations were collected at the time of sacrifice. The day after the last dose, the surviving animals were sacrificed and gross and microscopic pathologic examinations conducted.
No drug-related effects were noted upon clinical observation. High-dose male rats (but not females) exhibited slightly decreased feed intake and rate of weight gain. No drug-related changes were noted upon ophthalmological examination. Likewise, gross and microscopic pathologic examinations revealed no drug-related effects.
No drug-related effects were present at dosages up to and including 4 mg/kg/day. Drug-related effects were seen for males at 8 mg/kg/day. No drug-related effects were present for females at any dose. Therefore, the no-observed-effect level for laidlomycin propionate in rats was 4 mg/kg/day for males and 8 mg/kg/day for females.
Cardiovascular effects of laidlomycin propionate in anesthetized dogs. Laidlomycin propionate was administered at dosage levels of 100, 300, and 1000/mcg/kg to four anesthetized dogs (2 male and 2 female). There was a significant increase in coronary artery blood flow following administration of the 1000/µg/kg dose. No other significant hemodynamic changes were observed. Laidlomycin propionate, at doses of 10, 30, and 100/mcg/kg, was administered intravenously to four anesthetized dogs (2 males and 2 females). Laidlomycin propionate produced no significant changes in heart rate, myocardial conduction (as measured by the P-R interval of the ECG), systemic vascular resistance, or serum electrolytes (K+, Na+, and Ca+ +) at any of the doses tested. Only minimal effects on blood/gases were observed. Laidlomycin propionate caused significant, transient increases in coronary arterial blood flow at 30/mcg/kg, but had no other significant hemodynamic effects at this dose. Following the 100/µg/kg dose, significant increases in coronary arterial blood flow, cardiac output, aortic blood pressure, pulmonary arterial blood pressure and myocardial contractility (dP/dt) were observed.
These data indicate that the dog is at least 3-fold less sensitive to laidlomycin propionate administered by intraduodenal gavage compared with intravenous administration.
Study 9-D-82 - Subchronic toxicity in dogs.
Five groups, each composed of 4 males and 4 females, were administered doses of 0 (vehicle), 0.25, 0.5, 1.0, or 2.0 mg laidlomycin propionate per kilogram of body weight. Laidlomycin propionate was dissolved in the vehicle (90% propylene glycol)just before use. Doses were administered orally by stomach robe twice daily for 3 months (91 days). Therefore, the total doses were 0 (vehicle), 0.5, 1.0, 2.0, or 4.0 mg/kg/day. For each dog, the daily dose was adjusted to its weekly body weight. Clinical observations and body weights were recorded weekly. Additional examinations were given as follows:
|Examination||Predose||Second Month||Third Month|
*Selected animals examined on study day 29.
The day after the last dose, the surviving animals were necropsied.
Clinical signs attributed to laidlomycin propionate occurred for 1 male and 2 female dogs that received the highest dose, 4 mg/kg/day. These signs were (primarily) salivation, ataxia, body tremors, unthriftiness, wasting, and/or collapse. Due to the severity and nature of the clinical signs, the 2 female dogs were sacrificed during study weeks 3 and 5. No drug-related changes occurred in the body weight of those animals that survived until their scheduled necropsy. No drug-induced ocular toxicity was present. Although prominent retinal vascular patterns were observed in all treatment groups except the vehicle-control group, these retinal changes were considered most likely to be due to a transient physiologic effect and not due to toxicity. No drug-induced electrocardiographic changes occurred. Preliminary neurological examination of selected dogs on study day 29 revealed that several high-dose animals appeared to exhibit neurological deficits in certain parameters: biceps reflex, triceps reflex, femoral reflex, and/or proprioception. No drug-related effects, however, were present when all dogs received complete neurological examinations during the third month of treatment.
No drug-related differences in hematological parameters occurred in surviving animals. In the 2 high-dose females sacrificed due to poor clinical condition, lymphocytes were decreased and total erythrocyte count, neutrophils, hemoglobin, hematocrit, and/or leukocytes were increased. No drug-related differences in serum chemistry parameters occurred in the surviving animals. The 2 high-dose females sacrificed because of poor clinical condition exhibited elevated urea nitrogen, glutamic pyruvic transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, a-hydroxybutyric dehydrogenase, lactic dehydrogenase, and/or globulin.
No drug-related changes in urinary parameters were present, with the possible exception of lowered urine osmolality of high-dose males during the third month of treatment. Pathologic changes attributable to laidlomycin propionate occurred only at the highest dose of 4 mg/kg/day. These findings consisted of peripheral neuropathy in 3 males which survived to scheduled termination of the study and in 1 female which was sacrificed early because of poor clinical condition. The no-observed-effect level of laidlomycin propionate given orally twice a day to beagle dogs was 2 mg/kg/day.
Study 36-D-86 - Chronic Toxicity in Dogs.
Four groups, each composed of 6 male and 6 female beagle dogs, were administered 0 (vehicle), 0.375, 0.75, or 1.5 mg/kg twice daily (morning and afternoon) for a total dose of 0, 0.75, 1.5, or 3.0 mg/kg/day of laidlomycin propionate. Vehicle or 7.5-mg/ml solutions were administered into the oral cavity for 52 weeks. At the initiation of dosing, the dogs were 2 to 4 months of age. All animals were necropsied and selected tissues examined microscopically.
No drug effect occurred in the results of the ophthalmologic examinations conducted after approximately 3, 6, or 9 months of dosing. At the 12-month examination, 1 mid-dose female and 2 high-dose female animals had an occasional cell in the aqueous humor which may represent a drug effect. No evidence of ocular pathology was observed upon microscopic examination.
Dose-related neurologic abnormalities were present in mid- and high-dose males and females. All of the 12 dogs in the high-dose group and at least 6 of the 12 mid-dose dogs had neurologic deficits. The control and low-dose dogs showed no evidence of neurologic abnormalities. The number of dogs affected tended to increase during the first 3 months and then the number tended to stabilize. The major neurologic abnormalities detected were decreased/absent panniculus reflex, decreased/absent tendon reflexes, labored respiration, and paresis.
The no-observed-effect level for laidlomycin propionate administered orally to beagle dogs for 1 year was 0.75 mg/kg/day. After doses of 1.5 and 3.0 mg/kg/day, dose-related neurologic deficits, increased serum triglyceride levels, increased liver and heart weights due to formation of vacuoles containing glycogen, and skeletal and nerve fiber vacuolation were observed.
Study 38-R-86 - Two-Generation Reproduction Study in Rats
Four groups, each composed of 30 males, were administered vehicle or laidlomycin propionate in their diet beginning 10 weeks prior to cohabitation with treated females until after weaning of the F1 offspring. Four groups, each composed of 30 females, were administered vehicle or laidlomycin propionate in their diet beginning 2 weeks prior to cohabitation with treated males until after weaning of the F1 offspring. Concentrations of laidlomycin provided in the diet were 0, 50, 100, or 300 ppm for the vehicle-control, low-, mid-, and high-dose groups, respectively. One male and 1 female from the same dose group were cohabitated and the females were examined daily for positive evidence of mating. The day evidence of mating was observed was considered day 1 of gestation. On postpartum day 4, all F1 litters were culled to 10 pups, 5 males and 5 females when possible. Observations of F1 pups were noted until weaned 21 days postpartum. All pups that died during the first 10 days after parturition were examined for external anomalies. Pups that died after day 10 were necropsied. After all pups were weaned, 30 male and 30 female pups per group were selected randomly as P2 breeders, and 10 males and 10 females per group were selected randomly for necropsy (altered tissues were preserved). The remaining F1 pups were euthanatized.
P2 breeders were administered the same diet as their parents. At approximately 13 weeks of age, each P2 male was cohabited with 1 P2 female of the same dose group for 1 week. The P2 breeders remained on their laidlomycin propionate-containing or placebo diet until their scheduled termination after observations of the F2 litters were completed at 21 to 23 days postpartum. At this time, 1 F2 pup of each sex in each litter was selected randomly for necropsy (altered tissues were preserved) and the remaining pups were examined externally. All F2 pups that died during the first 10 days after parturition were examined for external and visceral anomalies.
P1 males received an average of 0, 3.8, 7.6, and 23.6 mg of laidlomycin propionate per kilogram of body weight per day in the vehicle-control, low-, mid-, and high-dose groups, respectively. One mid-dose male was killed in a moribund condition and its death was considered unrelated to drug administration. Treatment with laidlomycin propionate did not affect the clinical condition or fertility of these animals. After 2 to 10 weeks of dosing, the high-dose males had lower body weights than vehicle-control males. No drug effect was noted at necropsy or in the histopathologic examination results of grossly altered tissues.
P1 females in the vehicle-control, low-, mid-, and high-dose groups received an average of 0, 4.2, 7.1, and 25.8 mg/kg/day of laidlomycin propionate, respectively. Treatment with laidlomycin propionate did not affect the incidence of pregnancy, length of gestation, live litter size, or gestation index. Drug-related effects in pregnant high-dose females consisted of a wasting (decrease in physical bulk) clinical condition from approximately 14 days postparturition until scheduled necropsy and significantly decreased body weights between approximately 7 days postparturition through scheduled necropsy. One low-dose female was found dead approximately 2 weeks postparturition. The cause of death was considered unrelated to drug administration. At necropsy, no drug-related effects were present in PI females that littered (necropsied after approximately 9 weeks of drug administration) or in P1 females that did not litter (necropsied after approximately 6 weeks of drug administration).
Treatment with laidlomycin propionate did not affect the survival indices of the F1 pups at 1, 4, 7, 14 or 21 days (lactation index) postpartum. At postpartum days 14, and 21, the mean body weight of the male and female pups from the high-dose dams were significantly lower than controls. No pups had laidlomycin propionate-related anomalies.
P2 males in the vehicle-control, low-, mid-, and high-dose groups received an average of 0, 5.6, 11.7, and 38.3 mg/kg/day of laidlomycin propionate, respectively. The high-dose males had significantly decreased body weights compared with vehicle-control males from weaning until cohabitation and at necropsy. Although not considered an adverse effect, the low-dose males had significantly increased body weights from 2 weeks postweaning until cohabitation and at necropsy. No drug effect was noted at necropsy or in the histopathologic examination results of grossly altered tissues.
P2 females in the vehicle-control, low-, mid-, and high-dose group received an average of 0, 5.2, 10.8, and 36.4 mg/kg/day of laidlomycin propionate, respectively. Treatment with laidlomycin propionate did not affect the incidence of pregnancy, length of gestation, live litter size, or gestation index. Drug-related effects in pregnant high-dose females consisted of a wasting and unthrifty clinical condition from approximately 7 days postparturition to scheduled necropsy. From weaning until termination, the high-dose females had significantly decreased body weights compared with vehicle-control females. A decrease in food intake in high-dose females also occurred during this time. Although not considered an adverse effect, 15 to 22 days after positive evidence of mating was detected, low-dose pregnant females had significantly higher body weights than vehicle-control pregnant females. At necropsy 2/30 mid- and 9/30 high-dose females had intestinal fecal impaction. No histopathologic change in the gastrointestinal tract was observed that could be associated with the fecal impaction.
Treatment with laidlomycin propionate did not affect the survival indices of the F2 pups at 1, 4, 7, 14, or 21 days (lactation index) postpartum. From 7 through 21 days postpartum the high-dose group had an increased incidence of unthrifty and inactive pups. At postpartum days 7, 14, and 21, the mean body weight of the male and female pups from the high-dose dams were significantly lower than controls. No pups had laidlomycin propionate-related anomalies.
It is concluded that treatment with laidlomycin propionate did not affect reproduction and fertility variables in either generation in either sex of rat. The no-effect-level for treatment related decreases in body weights in PI males and females and F2 males and females was 300 ppm.
Study 25-R-82 - Teratology in Rats.
Four groups, each composed of 25 female rats with evidence of mating, were administered individual doses of 0 (vehicle), 1, 2, or 4 mg laidlomycin propionate/kg body weight. The day evidence of mating was found was considered gestation day 1. Animals were dosed from days 7 through 16 of gestation. laidlomycin propionate was dissolved daily in the vehicle (90 % propylene glycol)just before use. Doses were administered by gavage in volumes of 1 ml/kg body weight using a metal rodent incubator. Daily doses for gestation days 7 through 12 and 13 through 16 were based on body weights recorded on gestation days 7 and 13, respectively. Clinical observations and body weights of individual animals were recorded on gestation days 1, 7, 13, and 21. On gestation day 21, the dams were necropsied, and the fetuses were subjected to teratologic evaluation.
No drug-related changes were noted in the clinical condition of the dams. A biologically significant reduction in maternal body weight (approximately 10%) was observed in the high dose group. The total numbers of live fetuses examined for teratologic changes were: 227 (22 litters) in the vehicle-control group; 249 (25 litters) in the low-dose group; 222 (22 litters) in the mid-dose group; and 241 (23 litters) in the high-dose group. All fetuses were resorbed from one dam in the highest dose group while there were no total resorptions in the control-, low-, or mid-doses. Other maternal indices such as live letter size, fetal weight, corpora lutea, and indices for gestation survival, resorption, and implantation did not show drug related toxicities. Daily oral administration of laidlomycin propionate in dosages up to and including 4.0 mg/kg/day during the period of organogenesis was not teratogenic in rats. A no effect level of 2.0 mg/kg/day was found for laidlomycin propionate based on the lack of embryotoxicity, fetotoxicity, or teratogenicity.
Study 24-B-82 - Teratology in Rabbits. Four groups, each composed of 20 artificially inseminated female Dutch belted rabbits, were administered individual doses of 0 (vehicle), 1, 2, or 4 mg laidlomycin propionate/kg body weight. The day of insemination was considered gestation day 1. Animals were dosed from days 7 through 19 of gestation. Doses were administered by gavage in volumes of 1 ml/kg body weight using a metal rodent intubator. Daily doses for gestation days 7 through 12 and 13 through 19 were based on body weights recorded on gestation days 7 and 13, respectively. Clinical observations and body weights of individual animals were recorded on gestation days 1, 7, 13, 19, 25, and 29. On gestation day 29, the dams were necropsied, and the fetuses were subjected to teratologic evaluation.
No drug-related changes were noted in the clinical condition of the dams. An approximate decrease in body weight gain occurred at 4 mg/kg/day. One vehicle-control dam aborted and was euthanatized on the day prior to scheduled sacrifice. The abortion was attributed to spontaneous conditions and not to the experimental regimen. Two high-dose dams died and one was sacrificed due to poor clinical condition prior to scheduled sacrifice. The deaths were considered to be due to inhalation of laidlomycin propionate formulation during dosing. No drug-related changes occurred in any of the maternal indices: live-litter size, fetal weight, resorptions (early, late, and total), implantations, corpora lutea, Gestation Survival Index, Resorption Index, and Implantation Index. In addition, no drug-related changes were noted upon gross or microscopic pathologic examination of the dams. No drug-related teratologic changes were noted upon external, skeletal, and visceral examinations of the letuses. The total numbers of live fetuses examined for teratologic changes were: 51 (14 litters) in the vehicle-control group; 80 (19 litters) in the low-dose group; 59 (13 litters) in the mid-dose group; and-27 (9 litters) in the high-dose group. The total number of pregnant animals in each group was 17 in the vehicle-control group, 19 in the low-dose group, 15 in the mid-dose group, and 14 in the high-dose group. Daily oral administration of laidlomycin propionate in dosages up to and including 4 mg/kg/day during organogenesis was not teratogenic in rabbits. A no effect level of 2.0 mg/kg/day was found for laidlomycin propionate based on the lack of embryotoxicity, fetotoxicity, or teratogenicity.
Study 904-Y-82 - Genotoxicity. Ames Assay.
Doses for the mutagenesis assays were selected from a preliminary study conducted on the test material at 14 doses from 1.22 to 10,000 mcg per plate using the strain TA-100. In this study, the test material was toxic to the indicator strain at 312.50 mcg per plate and higher as evidenced by the reduced number of revertants on the minimal media plates. These results were used to select seven doses for the mutagenicity assays with and without addition of $9 metabolic activation. Doses ranged from 4.88 to 312.5 mcg per plate. Both an initial and independent repeat mutation assay were conducted using three plates per dose for each assay with and without metabolic activation.
The results of the initial and independent repeat assays conducted on the test material at doses ranging from 4.8 to 312.5 µg per plate in the absence and presence of metabolic activation did not show increased numbers of his+ revertant colonies. The positive-control treatments in both the nonactivation and S9 activation assays induced large increases in the revertant numbers with all the indicator strains, which demonstrated the effectiveness of the S9 activation system and the ability of the test system to detect known mutagens. Laidlomycin propionate did not exhibit genetic activity in any of the assays conducted in this evaluation and was not mutagenic to the Salmonella typhimurium indicator organisms.
Study 908-Y-86 - Genotoxicity, CHO/H(3PRT Mutation Assay. Range-finding assays for assessing cytotoxicity were conducted at 0.1 to 1000 µg/ml with and without activation. Based on those results, the assay was conducted without activation at 10 to 150 mcg/ml, and then at 10 to 80 µg/ml. Concentrations of 100 to 500 µg/ml were tested with metabolic activation and then at 50 to 250 µg/ml.
The results of the assays conducted on the test material at dose levels of 10 to 80 µg/ml without metabolic activation and 50 to 250 µg/ml with metabolic activation were negative. Laidlomycin propionate was negative for inducing mutations in Chinese hamster ovary cells with and without metabolic activation.
Study 910-Y-82 - Genotoxicity, Primary Rat Hepatocyte Unscheduled DNA Synthesis Assay.
A preliminary study to select doses was conducted with the test material at concentrations from approximately 0.051 µg/ml to 1000 µg/ml. High toxicity to complete lethality was present at concentrations of 1010 µg/ml.
The results of the assay conducted on the test material at dose levels of 0.051 to 253 µg/ml were negative. Laidlomycin propionate did not exhibit genetic activity and did not cause DNA damage to rat hepatocytes under the test conditions.
b. Safe concentration of residues and withdrawal period.
The safe concentration of residues is given by the equation:
Safe concentration, ppm = Average human Weight, kg x NOEL, mg/kg/day Food factor for meat x Safety factor
The most sensitive species for laidlomycin propionate potassium was the dog, in which a NOEL of 0.75 mg/kg/day was observed during a one-year toxicology study. For data based
upon a one-year toxicology study, a safety factor of 100 is normally assumed. Therefore, a safe concentration of total residues of laidlomycin propionate in muscle is given by the equation:
Safe concentration, ppm = 60 x 0.75 = 0.9 ppm 0.5 x 100
Using appropriate consumption factors, the safe concentration of residues in other tissues are liver, 1.8 ppm; kidney, 2.7 ppm; and fat, 3.6 ppm. The estimated steady state concentration of drug-related residues in the liver of cattle consuming approximately 3.5 times the maximum approved daily dose of laidlomycin propionate potassium was 0.99 ppm. Consequently, the studies conducted with regard to human safety support a zero withdrawal for cattle fed laidlomycin propionate potassium.
c. Total Residue Depletion and Metabolism Study in Cattle - Study IAS 1109-380.
Twelve cattle (six steers and six heifers) were each given 14C-laidlomycin propionate potassium twice daily at a dose of 1 mg/kg BW/day for seven consecutive days. Based on either actual or predicted feed intake, this dose of laidlomycin propionate was approximately 2.5 times the dose that the animals would have received if laidlomycin propionate had been incorporated into the diet at its highest approved concentration. Animals (three at each time point) were slaughtered at 12, 24, 72, and 144 hours after the last dose and samples of liver, kidney, muscle, and fat were obtained from each animal. Samples of urine and feces were collected throughout the study from the three animals slaughtered at 144 hours after the last dose. The amount of 14C in each sample of tissue, urine and feces was determined by appropriate scintillation counting techniques.
An average of 86% of the administered radioactivity was recovered in feces and 0.32% was recovered in urine. Liver had the highest concentration of drug-related material, as illustrated in the table below.
|Time after last dose, h||Laidlomycin propionate-derived residue, ppm(a) - Liver||Laidlomycin propionate-derived residue, ppm(a) - Kidney||Laidlomycin propionate-derived residue, ppm(a) - Muscle||Laidlomycin propionate-derived residue, ppm(a) - Fat|
|12||.926 ± .004||.025 ± .003||.010 ± .004||.041 ± .009|
|24||.487 ±. 114||.022 ± .006||.005 ± .002||.032 ± .006|
|72||.166 ± .088||.017 ± .005||.003 ± .002||.030 ± .012|
|144||.087 ± .018||.010 ± .004||.004 ± .001||.037 ± .013|
(a) Values are mean±standard deviation.
The metabolites present in the livers from the cattle slaughtered at 12 hours and 24 hours after the last dose were determined by HPLC analysis of the material extracted with methanol. More than 95% of the residue was extracted, indicating very little protein-bound residue was present. The HPLC analysis of the liver extracts revealed laidlomycin and despropionyl laidlomycin were present as major metabolites. No laidlomycin propionate was found in the liver, and no other single metabolite represented more than 10% of the extractable residue.
d. Comparative Metabolism of Laidlomycin propionate in Dogs - Study BMS 8817.
A study to evaluate the metabolism of laidlomycin propionate in dogs was conducted, as the dog was identified as the most sensitive species in toxicology studies with the drug. Following a single, oral 2 mg/kg BW dose of 14C-laidlomycin propionate potassium to two dogs, 2% of the administered dose was excreted in urine and 83 % was excreted in feces. HPLC analysis revealed that laidlomycin, the most abundant component in cattle liver, was also present in relatively high proportion in the plasma, urine, and feces of the dog. No significant quantity of despropionyl laidlomycin was present in plasma.
The same two dogs were redosed with five oral 2 mg/kg BW doses of 14C-laidlomycin propionate potassium at 12-hour intervals. The dogs were sacrificed three hours after the last dose. HPLC analysis of the livers of the dogs indicated the presence of eleven metabolites, among which laidlomycin and despropionyl laidlomycin were minor metabolites. The other metabolites were not structurally identified. These metabolism studies with dogs demonstrated that dogs treated with laidlomycin propionate potassium were exposed to the same metabolites as those to which humans would be exposed upon consumption of tissues from treated cattle.
e. Marker Residue and Tolerance.
A marker residue and tolerance for residues of laidlomycin propionate in tissues of cattle were not assigned, as the total drug-related residues at zero withdrawal in cattle are well below safe concentrations of residues listed in Part 6b.
f. Withdrawal Time Assignment.
A pharmacokinetic analysis of the 14C-laidlomycin propionate residue data described in Part 6c, above (Study Report IAS 1109-380) was used to estimate the steady state level of laidlomycin propionate total residues in liver tissue. That analysis gave an estimated steady state level of 0.99 ppm at a "practical zero withdrawal" time of 12 hours at the 1 mg/kg BW (2.5X) dosing level used in that study. A zero withdrawal time was assigned for this drug use in cattle as the 0.99 ppm level is well below the 1.8 ppm safe concentration established for total residues of laidlomycin propionate in cattle liver tissue.
The pharmacokinetic approach used to estimate the steady state dosing level of laidlomycin propionate in liver considers-the separate contribution of each of the three phases of the depletion curve and is based on the principles discussed in a paper by Jacob et al. (T.A. Jacob, R.F. Alvaro, L.R. Chapin, M.L. Green, H.T. Meriwether, G. Olsen, A.A. Van Iderstine, and F.J. Wolf, J. Agric. Food Chem., 30, 248 (1982)). The use of this approach to estimate the steady state dosing level in liver was justified because almost all of the drug related residue was extractable and the residue depletion curve of the data in Study Report IAS 1109-380 was adequate to allow the pharmacokinetic analysis of those data.
g. Regulatorv Methods for Residues. A regulatory analytical method for the measurement of residues of laidlomycin propionate in the tissues of cattle was not required, as total drug related residues at zero withdrawal in cattle are well below the safe concentrations of residues listed in Part 6b.
h. The Effect Of Long Term Use Of Laidlomycin Propionate On Development Of Antibiotic Resistance and on the Salmonella Reservoir in the Target Species.
Study IAS 1109-C863 - Antimicrobial resistance Of indigenous fecal coliforms.
A study was conducted by D.J. Fagerberg, Colorado Animal Research Enterprises, Inc., Ft. Collins, CO which evaluated the effect of feeding laidlomycin propionate at 12.2 g/ton of total diet (80 mg/head/day) upon antimicrobial resistance of fecal coliforms in young calves. Fecal samples from 8 treated calves and 8 nontreated calves were collected four times prior to treatment initiation to obtain baseline data, and weekly thereafter during an 8-week treatment period. Ten coliform isolates per calf per treatment period sampling were tested for susceptibility to amikacin, ampicillin, carbenicillin, cefoxitin, chloramphenicol, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfadiazine, tetracycline and trimethoprim/sulfamethoxazole. Continuous feeding of laidlomycin propionate over the 8-week period did not impact indigenous fecal coliform antimicrobial resistance.
Study IAS 1109-C874 - Tissue concentrations, antimicrobial resistance and shedding of Salmonella typhimurium.
A study was conducted by D.J. Fagerberg, Colorado Animal Research Enterprises, Inc., Ft. Collins, CO which evaluated the effect of feeding laidlomycin propionate at 11.8 g/ton of total diet (80 mg/head/day) to calves experimentally colonized with Salmonella tvphimurium on Salmonella shedding (prevalence, duration, and quantification), sequestering of salmonellae in tissues, and antimicrobial resistance of S. typhimurium. Following a 20-day facility acclimatization period, calves were fasted from feed and water for approximately 24 h and were then gavaged with an S. typhimurium culture. Feeding either a control diet or the diet containing laidlomycin propionate was initiated 5 days after Salmonella challenge and was continued for eight consecutive weeks. Eight calves were studied in the nonmedicated group, 7 were studied in the laidlomycin propionate group, and 4 calves served as environmental control animals. Fecal samples were collected from calves prior to challenge to assure freedom from indigenous salmonellae and for Salmonella detection and/or quantification 'twice during the 5-day postchallenge/pretreatment period and 16 times during the 8-week study period. At study end, all surviving Salmonella-challenged calves underwent surgical procedures to excise samples of liver, spleen and intestinal lymph node for analyses of the presence of test salmonellae. Five Salmonella isolates per calf (when available) from certain samplings were tested for susceptibility to amikacin, ampicillin, carbenicillin, cefoxitin, chloramphenicol, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfadiazine, tetracycline and trimethoprim/sulfamethoxazole. Laidlomycin propionate did not cause the quantity, duration, or prevalence of Salmonella shedding, Salmonella antimicrobial resistance, or Salmonella tissue sequestering to be different than that experienced in nonmedicated control calves.
VII. Agency Conclusions
This original NADA satisfies the requirements of section 512Co) of the Federal Food, Drug and Cosmetic Act, and demonstrates that laidlomycin propionate (Cattlyst®) when used under proposed conditions of use is safe and effective for the labeled indications. This production enhancing drug has been classified as 'OTC.' Its use does not raise any special safety concerns or require any diagnosis. Adequate directions for the layman's use have been included in the labeling.
Under section 512(c)(2)(F)(i) of the Federal Food, Drug and Cosmetic Act, this approval qualifies for five years of marketing exclusivity beginning on the date of approval because no active ingredient (including ester or salt of the active ingredient) has been approved in any other application.
VIII. Attached labeling
- The label for the Type A Medicated Article (Cattlyst®50) and
- Bluebird labeling for Type C Medicated Feeds.
Copies of applicable labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855
IX. Attached Method
High Pressure Liquid Chromatography Assay of Laidlomycin A Propionate Potassium, Laidlomycin B Propionate Potassium, and Laidlomycin A in Feeds with Labeled Strength of 5 to 124 ppm.