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U.S. Department of Health and Human Services

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NADA 138-992 MGA® 100/200 Premix, MGA® 500 Liquid Premix, Bovatec®, Tylan® - original approval

Approval Date: August 6, 1990

I. GENERAL INFORMATION:

NADA 138-992
Sponsor: The Upjohn Company
Agricultural Division
Generic Name: melengestrol acetate, lasalocid sodium, tylosin phosphate
Trade Name: MGA® 100/200 Premix, MGA® 500 Liquid Premix, Bovatec®, Tylan®
Marketing Status: Over the Counter (OTC)

II. Indications for Use:

For increased rate of weight gain, improved feed efficiency, suppression of estrus (heat), and reduced incidence of liver abscesses in heifers fed in confinement for slaughter.

III. Dosage Form, Route of Administration and Recommended Dosage:

Dosage Form: Feed

Route of Administration: Oral

Recommended Dosage: Approval has been granted to feed 0.25 to 0.5 mg melengestrol acetate (MGA) per head per day in combination with 10 to 30 g lasalocid per ton of air dried complete feed and 8 to 10 g tylosin per ton of air dried complete feed (to provide 90 mg/hd/day) when each additive is provided via separate supplements or a supplement containing melengestrol acetate is fed in combination with a complete feed containing lasalocid and tylosin.

The supplement containing melengestrol acetate provided at a rate of 0.5 to 2.0 pounds per head may be top-dressed onto or mixed with the feed containing lasalocid and tylosin.

This clearance does not provide for the mixing of melengestrol acetate, lasalocid and tylosin premixes together in a common supplement or in a complete ration offered for sale by the feed manufacturer.

IV. Effectiveness: (In compliance with combination approval claims)

The efficacy of melengestrol acetate for increased rate of weight gain, improved feed efficiency and suppression of estrus (heat) in heifers fed in confinement for slaughter is well documented and approved (21CFR 558.342). Further, the effectiveness of lasalocid for improved feed efficiency and increased rate of weight gain of feedlot cattle is established and approved (21CFR 558.311) as is the effectiveness of tylosin for reduction of liver abscesses in the same class of cattle (21CFR 558.625). For these applications, the efficacy of melengestrol acetate, lasalocid and tylosin when co-administered was established by conducting a series of field trials under a common protocol. These trials were designed to evaluate the performance of feedlot heifers fed each drug separately and in combination.

A. Pivotal Study

A feedlot heifer study consisting of field trials at nine locations with three replications per location was conducted to generate animal performance data on the combination of melengestrol acetate, lasalocid and tylosin. Results of each study are reported as well as a summary and statistical analysis of the pooled data from all nine field investigations.

  1. Type of Study

    a. Clinical (field) trials

  2. Investigator names and addresses by location:

    Trial No. 540-9665-0-JFM-83-002

    Steve Rust, Ph.D.
    Montana Ag Experiment Station
    Route 1, Box 131
    Huntley, MT 59037

    Trial No. 540-9665-0-JFM-83-003

    David Bechtol, D.V.M.
    Palo Duro Agri. Division
    Box 974
    Canyon, TX 79015

    Trial No. 540-9665-0-JFM-83-004

    Thomas R. Schriemer, B.S.
    Unit 9690
    The Upjohn Company
    Kalamazoo, MI 49001

    Trial No. 540-9665-0-JFM-83-005

    Steve Rust, Ph.D.
    Montana State University
    Bozeman, MT 59717

    Trial No. 540-9665-0-JFM-83-006

    Jack Riley, Ph.D.
    Dept. of Animal Science - Industry
    Weber Hall KSU
    Manhattan, KS 66506

    Trial No. 540-9665-0-JFM-83-007

    Richard Luther, Ph.D.
    Animal and Range Science Dept.
    Animal Science Complex Building
    Brooklings, SD 57007

    Trial No. 540-9665-0-JFM-83-008

    Jerry Martin, Ph.D.
    Panhandle State University
    Box 430
    Goodwell, OK 73939

    -and-

    Donald R. Gill, Ph.D.
    005 Animal Science
    Oklahoma State University
    Stillwater, OK 74074

    Trial No. 540-9665-0-83-009*

    Elvin Thomas, Ph.D.
    Dept. of Animal & Dairy Sciences
    Auburn University
    Auburn, AL 36830

    Trial No. 540-9665-0-JFM-83-010

    Wilton Heinemann, Ph.D.
    Research & Extension Center
    Washington State University
    P.O. Box 30
    Prosser, WA 99350

    Trial No. 540-9665-0-JFM-84-001

    Steve Schmidt, Ph.D.
    Dept. of Animal and Dairy Sciences
    Auburn University
    Auburn, AL 36830

    *This trial was canceled shortly after it was started for reasons unrelated to the safety and efficacy of the compounds. There were no data generated as a result of this trial.

  3. General design of each field investigation

    1. Purpose of the field investigation:

      To evaluate the effect of melengestrol acetate, lasalocid sodium and tylosin phosphate on the performance of feedlot heifers when fed singly and in combination.

    2. Test animals

      (1) Species: Bovine
      Number/group: The number of heifers per treatment group varied from location to location, and ranged from 6 to 14 animals per pen (Table 1).

      (2) Subgroup Identity: Heifers used in the field studies were non-pregnant yearlings and the breeds were typical of those commonly found in commercial feedlots. The average initial weights ranged from 674 to 826 pounds (Table 1).

    3. Control groups

      Groups of heifers fed melengestrol acetate, or lasalocid or tylosin alone, or lasalocid and tylosin in combination served as controls. Pairwise, comparisons were made to groups of heifers for the 3 drugs in combination.

    4. Diagnosis: Not applicable.
    5. Dosage form:

      (1) Medicated feed: Feed was medicated using melengestrol acetate, lasalocid or tylosin premixes. Final feeds were prepared using intermediate premixes which were either mixed into or top-dressed onto the bulk of the ration.

    6. Route of drug administration:(1) Oral
    7. Dosages:

      The dosages used in the field study were: melengestrol acetate, 0.5 mg/head/day; lasalocid, 30 gm/ton of air dried feed; tylosin, 10 gm/ton of air dried feed.

    8. Days on test:

      The cattle were fed for a minimum of 90 days, the actual day of trial termination being left up to the investigator's judgement as to when the cattle had reached market weight and condition. The days on test by location are listed on Table 1.

      (Eds. note: The following table consists of 5 columns.)

      Table 1.  General Trial Information
                                                Mean                          Estrus
      Location                                Starting                      Detection
      Trial No.               Number/Pen       Wt/lbs       Days on Test     (Yes/No)
      Montana (Huntley) (A)                                                                      
      (540-9665-0-JFM-83-002          12              790               102              Yes            
      Texas                                                                                      
      540-9665-0-JFM-83-003           14              707               104              Yes            
      Michigan                                                                                   
      540-9665-0-JFM-83-004            8              735                97              No             
      Montana (Bozeman) (B)                                                                      
      540-9665-0-JFM-83-005            8              826                97              Yes            
      Kansas                                                                                     
      540-9665-0-JFM-83-006            6              731                92              No             
      South Dakota                                                                               
      540-9665-0-JFM-83-007            8              700               126              No             
      Oklahoma                                                                                   
      540-9665-0-JFM-83-008            8              674               112              Yes            
      Washington                                                                                 
      540-9665-0-JFM-93-010            8              773                96              Yes            
      Alabama                                                                                    
      540-9665-0-JFM-001               8              728                99              No  
      
  4. i. Measurements taken: The following were measured

    • Estrus: 2X per day (AM and PM) during days 5 through 47 of the trial. Estrus was measured at five of the nine locations (Table 1).
    • Cattle weight: Cattle were weighed at about 28 day intervals.
    • Feed consumption: Daily feed records were maintained.
    • Daily observations: Individual pens of cattle were observed at least once per day for general activity and physical condition of the cattle.
    • Liver Evaluation: Individual heifer livers were evaluated for liver abscesses at slaughter.
  5. Results

    Performance Data:

    The treatment by location means for percent standing estrus, average daily gain, feed efficiency and percent abscessed livers are presented in the following tables. While the study included several treatment groups, data from only those pertinent to the subject approval are included.

    (Eds. note: The following table consists of 6 columns.)

    Table 2. Treatment by Location Means for Percent Standing Estrus

    Treatment Oklahoma Montana* Montana** Texas Washington
    melengestrol acetate/tylosin 8.33 16.67 16.67 26.19 8.33
    melengestrolacetate
    /lasalocid sodium
    8.33 16.67 11.11 11.90 16.67
    lasalocid sodium/tylosin 45.83 36.31 61.11 19.05 37.50
    melengestrolacetate/
    lasalocid sodium/ tylosin
    4.17 16.67 8.33 7.14 8.33

    * Bozeman, Montana
    ** Huntley, Montana

    (Eds. note: The following 3 tables consists of 10 columns each.)

    Table 3. Treatment by Location Means for Average Daily Gain

    Treatment Alabama Oklahoma Kansas Montana* Montana** S Dakota Texas Michigan Washington
    melengestrolacetate/tylosin 2.63 2.39 3.17 2.40 2.93 3.19 2.92 3.42 2.52
    melengestrol acetate
    /lasalocid sodium
    3.05 2.38 3.09 2.43 2.87 3.31 3.15 3.45 2.59
    lasalocid sodium/tylosin 2.91 2.10 2.99 2.44 2.60 3.05 2.61 3.04 2.36
    melengestrol acetate
    /lasalocid sodium/tylosin
    3.03 2.28 3.21 2.61 3.00 3.32 2.89 3.42 2.78

    * Bozeman, Montana
    ** Huntley, Montana

    Table 4. Treatment by Location Means for Feed Efficiency Treatment Alabama Oklahoma Kansas Montana* Montana** S Dakota Texas Michigan Washington melengestrol 8.53 6.25 8.19 10.42 9.03 6.53 7.49 6.85 8.49 acetate/tylosin melengestrol 7.47 6.19 8.02 10.07 9.14 9.56 7.26 6.93 8.17 acetate/lasalocid sodium lasalocid sodium/tylosin 7.68 6.79 8.36 10.43 9.67 6.78 8.29 7.29 8.60 melengestrol 7.49 6.43 7.74 9.84 8.88 6.37 7.63 6.77 7.83 acetate/lasalocid sodium/tylosin * Bozeman, Montana ** Huntley, Montana

    Table 5. Treatment by Location Means for Percent Abscessed Livers Treatment Alabama Oklahoma Kansas Montana* Montana** S Dakota Michigan Washington melengestrol 12.50 0.00 0.00 8.33 11.11 4.17 0.00 8.33 acetate/tylosin melengestrol 29.17 16.67 33.33 54.17 19.44 8.33 8.33 12.50 acetate/lasalocid sodium lasalocid sodium/tylosin 8.33 0.00 5.56 13.69 8.33 0.00 0.00 26.19 melengestrol 16.67 0.00 5.56 25.00 19.44 0.00 0.00 12.50 acetate/lasalocid sodium/tylosin * Bozeman, Montana ** Huntley, Montana

    The results from the 9 individual field investigations were pooled and analyzed statistically to evaluate effectiveness. Average daily gain (ADG), feed efficiency (FE) (9 locations), and liver abscess data (8 locations) were pooled. Estrus suppression data were pooled from five of the nine locations.

    The least squares treatment means pooled across all locations are presented in Table 6.

    (Eds. note: The following table consists of 5 columns.)

    Table 6. Least Squares Treatment Means Pooled Across Location

                                % Standing       Feed          Average     % Abscessed
        Treatment                 Estrus*     Efficiency      Daily Gain      Livers*
    melengestrol acetate/tylosin       23.89           7.97              2.84           16.19        
    melengestrol acetate/lasalocid     22.41           7.76              2.92           27.94        
    sodium                                                                                    
    lasalocid sodium/tylosin           39.66           8.21              2.68           17.39        
    melengestrol acetate/lasalocid     17.98           7.66              2.95           17.76        
    sodium/tylosin                                                                            
    *Means are based on Freeman-Tukey transformation.
    
  6. Statistical analysis: 

    A least squares analysis of variance for the transformed liver abscess (8 locations) and performance data from the nine location, and transformed estrus data from 5 locations was conducted. The results of this analysis are presented on Table 7.

    (Eds. note: The following table consists of 6 columns.)

    Table 7. The significance levels for the comparisons required for the combinations were:

                                                         ------------Parameter------------
                                                                                        Liver
        Combination            Comparison              Estrus       FE      ADG        Abscess
    MGA + Lasalocid(L) + T    MGA + L vs MGA + L + T                                              .00021   
                              MGA + T vs MGA + L + T                      .00531   .02985             
                              L + T vs MGA + L + T           .000012      .00001   .000005 
    

    The melengestrol acetate + lasalocid + tylosin combination was justified since the contribution of lasalocid significantly enhanced feed efficiency (P=0.00531). In this combination, melengestrol acetate was effective for estrus suppression (P=0.000012), feed efficiency (P=0.00001), and average daily gain (P=0.000005). Tylosin was also effective in reducing the incidence of liver abscesses (P=0.00021) in this 3-way combination (Table 7).

  7. Conclusions

    The data generated by the nine location field study demonstrated that the melengestrol acetate, lasalocid, tylosin combination is justified for its effect on estrus suppression, improved feed efficiency, increased rate of weight gain and reduction of liver abscesses. Each drug, melengestrol acetate, lasalocid and tylosin has been shown to make a significant contribution to the effectiveness of the combination.

  8. Adverse Reactions

    No adverse reactions due to the feeding of melengestrol acetate, lasalocid, or tylosin, either singly or in combination were reported.

  9. Special Issues

    Compliance with combination drug policy:

    a. The effectiveness and safety of melengestrol acetate, lasalocid, and tylosin when fed singly to feedlot cattle are well documented in their respective approved NADAs. The results of effectiveness and safety studies were submitted to the FDA in support of these respective NADAs. Such data resulted in the approval of melengestrol acetate as per CFR 558.342, lasalocid as per CFR 558.311, and tylosin as per CFR 558.625. Data generated in support of combination usage have demonstrated that melengestrol acetate, lasalocid and tylosin fed together are effective and safe.

    The data establish compliance with 21CFR 514.1(b)(8)(v) and CVM's combination drug guidelines (November 9, 1983). The combination is justified as detailed in items 4, 5 and 6 above.

    The use of untreated controls was not deemed necessary as a test for general effectiveness because the individual drugs have been previously shown to be effective and already approved at the levels tested. The treatment groups consisting of the individual drugs and the two-way combinations served as the appropriate controls for the respective three-way combination. Thus, these treatment groups essentially served as negative controls with respect to 21CFR 514.111 (a)(5)(ii)(a)(4), and the studies were properly controlled.

    To justify the combination, comparisons were made which demonstrated that each drug made a statistically significant contribution to the combination. The three-way combination provides a benefit that cannot be obtained from any of the possible two-way combinations.

    A comparison of melengestrol acetate-lasalocid-tylosin vs. melengestrol acetate-lasalocid for transformed percent liver abscesses demonstrates the contribution of tylosin to the combination.

    A comparison of melengestrol acetate-lasalocid-tylosin vs. lasalocid-tylosin for ADG, FE and estrus suppression demonstrates the contribution of melengestrol acetate to the combination. Significance for any variable shows that melengestrol acetate contributes to the combination.

    A comparison of melengestrol acetate-lasalocid-tylosin vs. melengestrol acetate-tylosin for ADG and FE demonstrates the contribution of lasalocid to the combination. Significance for any variable shows that lasalocid contributes to the combination.

    The proposed ranges for each drug are justified when fed in combination since the highest levels proposed were tested in combination for efficiency and human and animal safety.

B. Corroborative Studies: N/A

V. Animal Safety:

A. Pivotal study

The safety of melengestrol acetate, lasalocid and of tylosin in the bovine have been documented as evidenced by their respective approvals (21CFR 558.342 for melengestrol acetate, 21CFR 558.311 for lasalocid, and 21CFR 558.625 for tylosin) as feed additives. The following pivotal study was conducted to establish the target animal safety of these three additives when fed in combination.

  1. A 90 day, subchronic study was conducted.
  2. Investigator:

    A.D. Hall, Ph.D., D.V.M.
    The Upjohn Company
    Kalamazoo, MI 49001

  3. General Study design:

    1. Purpose:

      The purpose of this study was to evaluate the safety of the melengestrol acetate, lasalocid and tylosin when fed in combination in the diet of yearling heifers at 1 to 5 times the recommended dosage.

    2. Test animals:

      1) Species: Bovine
      Number per Group: 14 control, 7 treated.

      2) Breed: Hereford
      Age: Yearling
      Sex: Female (heifers)
      Weight: 284 to 378 kg initial weight

    3. Dosage form:

      1) Drug premixes were incorporated in the feed through the use of intermediate premixes.

      2) Formulations were typical of those used in commercial feedlot.

    4. Dosage used:

      1) Control: No drugs

      2) 1X: 0.5 mg melengestrol acetate per head per day

      30 g lasalocid sodium per ton of air dried feed
      10 g tylosin phosphate per ton of air dried feed

      3) 3X: 1.5 mg melengestrol acetate per head per day

      90 g lasalocid sodium per ton of air dried feed
      30 g tylosin phosphate per ton of air dried feed

      4) 5X: 2.5 mg melengestrol acetate per head per day

      150 g lasalocid sodium per ton of air dried feed
      50 g tylosin phosphate per ton of air dried feed

    5. Routes of administration: Oral
    6. Test duration: 90 days
    7. Parameters measured:

      1) Clinical observations included twice daily health checks, daily observations, body weight, daily feed consumption.

      2) Clinical pathology

      The following hematology parameters were measured:

      • Total leukocyte count
      • Total erythrocyte count
      • Hemoglobin
      • Hematocrit
      • Mean corpuscular volume
      • Mean corpuscular hemoglobin
      • Mean corpuscular hemoglobin concentration
      • Platelets

      Microscopic Examination: WBC differential

      The following serum chemistry parameters were measured:

      • Aspartate aminotransferase
      • Alkaline phosphatase
      • Creatinine
      • Inorganic Phosphorus
      • Glucose
      • Blood Urea Nitrogen
      • Calcium
      • Cholesterol
      • Total Bilirubin
      • Total Protein
      • Albumin
      • Creatinine phosphokinase
      • Sodium
      • Potassium
      • Chloride
      • Sorbitol dehydrogenase

      Urine specimens were collected via paracentesis from the urinary bladder at the time of necropsy. The following parameters were measured:

      Specific gravity
      Dipstick:

      • pH
      • Protein
      • Glucose
      • Ketones
      • Bile

      Microscopic Examination: Formed elements

      3) Gross and microscopic pathology

      The following is a list of organs and tissues that were examined grossly and had a representative sample fixed in 10% neutral buffered formalin for microscopic evaluation:

      • Brain
      • Pituitary
      • Thyroids
      • Adrenals
      • Pancreas
      • Ovaries
      • Uterus
      • Mammary gland
      • Mediastinal lymph node
      • Mesenteric lymph node
      • Lung
      • Liver
      • Kidneys
      • Urinary bladder
      • Spleen
      • Gross lesions
      Diaphragm
      • Rumen
      • Reticulum
      • Omasum
      • Abomasum
      • Duodenum
      • Jejunum
      • Ileum
      • Cecum
      • Colon
      • Heart (one section from each atrium and ventricle)
      • Gall bladder
      • Aorta (and small arteries)
      • Bone
      • Bone Marrow (smear)*

      *Bone marrow smears were made at the time of necropsy, air dried and fixed for 30 seconds or more in methanol. Slides were stained with Wrights stain.

      The following organs were weighed at necropsy, paired organs weighed together:

      Adrenals, liver, kidneys and heart.

      4) Results

      1. Clinical Observations

        No adverse, drug-related clinical signs were observed during this study. Although there were no significant differences in average daily gain (ADG) between treated and control animals at mid-study and at termination, there was a trend toward decreased ADG at the 3X and 5X levels of treatment.

      2. Clinical pathology

        Occasional statistically significant changes in several hematologic and serum chemistry parameters were detected, but all values were well within normal acceptable ranges and no dose-related trends were seen.

      3. Gross and microscopic pathology

        Several gross and histologic tissue changes were observed, but due to the relative even distribution of the changes in all dose groups including controls, these findings were considered to be incidental rather than drug- related.

      5) Conclusions

      Based upon the results of this study, the combination of melengestrol acetate, lasalocid and tylosin phosphate in the daily feed of yearling heifers appears to be non-toxic when fed for 90 days at up to 5 times the recommended dose.

VI. Human Safety:

A. Drugs for use in food animals

  1. Toxicity tests

    Data regarding toxicity testing in melengestrol acetate, lasalocid sodium and tylosin phosphate are contained in the approved NADAs for the three above mentioned compounds.

  2.  Safe concentration of residues

    Tolerances for melengestrol acetate, lasalocid sodium and tylosin phosphate are published in the Code of Federal Regulations. Melengestrol acetate is currently approved under 21CFR 558.342 for use in heifers at 0.25 to 0.50 mg/head/day with a 48 hour withdrawal period. No residues of melengestrol acetate may be found in uncooked edible tissues of cattle with a method sensitive to 25 ppb (21CFR 556.380). The tolerance for lasalocid in edible tissue of cattle under 21CFR 556.347 is 0.7 ppm with no withdrawal period established for cattle under 21CFR 558.311. The tolerance for tylosin phosphate has been established at 0.2 ppm (negligible residue) in uncooked fat, muscle, liver and kidney (CFR 556.740). Tylosin phosphate has no withdrawal period established under 21CFR 558.625.

  3. Residue depletion and metabolism studies

    Numerous studies have been conducted relative to the metabolism and depletion of residues of melengestrol acetate, lasalocid, and tylosin when administered individually to cattle. The results of those studies have been filed under the following submissions:

    (Eds. note: The following table consists of 3 columns.)

    Melengestrol Acetate     Lasalocid           Tylosin
        NADA 034-254            NADA 096-298         NADA  12-491              
        NADA 039-402                                 NADA 104-646              
        NADA 124-309                                                          
    
  4. Residue depletion noninterference study

    The following study was conducted to support the use of the three-way combination of melengestrol acetate, lasalocid sodium and tylosin phosphate in heifers:

    Location: Michigan

    Sponsor: The Upjohn Company

    Investigators:

    L.F. Krzeminski, Ph.D.
    The Upjohn Company

    P. R. Handy, Ph.D.
    Lilly Research Laboratories
    Greenfield, IN 46140

    G. Chen, Ph.D.
    Animal Science Research
    Hoffman-LaRoche
    Nutley, NJ 07110

    Groups of feedlot heifers were fed for 90 days with the drug combinations and treatment levels described below.

    (Eds. note: The following table consists of 4 columns.)

     
               Number of   Treatment
    Group       Animals      Level                  Treatment*
     1              14            0            Control                              
     2               7            1X           0.5 mg MGA + 30 g lasalocid + 10 g   
                                               tylosin                              
     3               7            3X           1.5 mg MGA + 90 g lasalocid + 30 g   
                                               tylosin                              
     4               7            5X           2.5 mg MGA + 150 g lasalocid + 50    
                                               g tylosin                     
    

    * Melengestrol acetate treatment expressed as mg/head/day, lasalocid and tylosin expressed as gram/ton air dried ration.

    The animals in each group were slaughtered within 16 hours following their last feeding. Perirenal fat was collected from all four treatment groups for the melengestrol acetate analysis, and liver samples were collected from the group 1 and 2 animals for the assay of lasalocid and tylosin.

    1. Residues of melengestrol acetate

      The samples of pererenal fat from each animals were assayed for residues of melengestrol acetate using the official AOAC gas chromatographic method. Analysis of the samples from the group 2 (1X) animals showed that all fat samples were below the 25 ppb tolerance for MGA and five of the seven samples were below the 10 ppb limit of reliable measurement of the assay. The two fat samples that gave positive responses had MGA levels of 12.7 and 13.7 ppb.

      Fat samples from groups 3 and 4 (the heifers dosed at 3X and 5X levels) yielded average residue levels of 37.6 and 49.4 ppm, respectively.

    2. Residues of lasalocid

      Liver tissue that was collected from the seven control animals and the seven heifers fed the group 2 (1X) ration were assayed for lasalocid by the HPLC -fluoresence regulatory method for the drug. An average residue value of 0.09 ppm (SD. 0.11 ppm) was obtained for the group 2 heifers, and that level is well below the 0.7 ppm tolerance for lasalocid in the livers from the control animals.

    3. Residues of tylosin

      The liver tissue samples from the group 2 (1X) heifers and 7 of the control animals were assayed for tylosin by the official assay which measures microbiologically the active drug. No positive responses were obtained for any of the samples by this method which has a limit of quantitation of 0.1 ppm.

  5. Assay noninterference data

    1. Melengestrol acetate assay

      Data were generated using spiked control fat tissue samples to demonstrate that the presence of residues of lasalocid and tylosin does not interfere with the assay for MGA. The study was also intended to show that MGA is stable in frozen fat tissue over a period of 60 days.

      Samples of freshly ground control bovine fat tissue were spiked with MGA, lasalocid and tylosin at the following levels:

      MGA: 0.025
      Lasalocid sodium: 7.0 ppm
      Tylosin phosphate: 1.0 ppm

      The spiked samples were assayed in duplicate for MGA by the official AOAC method after 0, 15, 30, 45, and 60 days of storage at -20°C. The average recoveries are shown below.

      (Eds. note: The following table consists of 8 columns.)

                          --------Day of Assay---------
                          0     15     30     45     60     Ave.     S.D.
       
       ppb found:          24.1   20.8    24.5    25.3    24.4     23.8               
       Percent Recovery    96     83      98     101      98       95        7.0
      
    2. Lasalocid assay

      Data demonstrating the noninterference of residues of melengestrol acetate on the HPLC-fluorescence detection assay for lasalocid were generated by Hoffmann-LaRoche to support the original NADA approval for lasalocid in cattle (NADA 96-298). Those data have also been published as a journal article (J. Agricultural and Food Chemistry , 31, 75-78 (1983)) and are summarized below.

      (Eds. note: The following table consists of 2 columns.)

      Recovery Values Obtained for Lasalocid from Spiked Control Liver Samples

      Drug Combination and Fortification Level     Lasalocid Recovery
       Lasalocid (0.1 ppm)                              86% (mean of 6 assays)                      
       Lasalocid (0.1 ppm) + tylosin (0.40 ppm)         85.0%                                       
       Lasalocid (0.1 ppm) + MGA (0.11 ppm)             80.1%    
    3. Tylosin assay

      Data to demonstrate that the presence of lasalocid and MGA does not interfere wit the assay of tylosin are contained in study S-AAC-84-03 conducted by the Elanco Products Company. Samples of liver from control heifers were composited and fortified with 0.2 ppm lasalocid, 0.2 ppm tylosin and 0.2 ppm MGA. The samples were assayed for tylosin by the cylinder plate microbiological method using Micrococcus luteus as the test organism. No interference was detected by the presence of lasalocid and MGA.

      The stability of tylosin in frozen liver tissue was demonstrated in study MRC8910 conducted by the Elanco Products Company. Liver tissue from control animals was fortified with 0.2 ppm tylosin and then frozen. Portions of the samples were thawed at intervals up to 56 days and assayed for tylosin. The stability of tylosin through 56 days was indicated by the recoveries in the following table:

      (Eds. note: The following table consists of 3 columns.)

      Tylosin Storage Stability in Frozen Liver

      Storage (days)        Mean Tylosin Recovery (ppm)         Percent Theorectical          
         0                   0.166                  83%                       
        14                   0.239                 114%                      
        28                   0.172                  86%                       
        56                   0.162                  81%            
      

      Regression analysis of these data demonstrates satisfactory tylosin stability for the period the tissues in the residue depletion study were stored before assay.

      The residue depletion and assay noninterference studies presented above demonstrate that the combined feeding of melengestrol acetate, lasalocid sodium, and tylosin phosphate at their highest approved levels results in tissue residues below the tolerance levels for each of the three drugs at 16 hours of withdrawal. The data also show that each drug in the three-way combination does not interfere with the assays for the others. This work confirms the adequacy of the 48 hour withdrawal time required for the presence of MGA in the combination and demonstrates that the use of these feed additives in combination does not pose a hazard to public health.

  6. Regulatory methods

    Practical analytical methods of analysis for tissue residues of melengestrol acetate, lasalocid sodium and tylosin phosphate may be found in the Food Additives Analytical Manual on display in FDA's Freedom of Information Public Room (Room 12-A-30), 5600 Fishers Lane, Rockville, MD 20857.

VII. Agency Conclusions:

These NADA's provide for the combination use of MGA, lasalocid sodium, and tylosin phosphate at the levels of 0.25 to 0.5 mg/head/day, 10 to 30 g/ton of feed, and 8 to 10 g/ton of feed (to supply 90 mg/head/day), respectively; for increased rate of weight gain, improved feed efficiency, suppression of estrus (heat), and reduced incidence of liver abscesses in heifers fed in confinement for slaughter. Adequate data were submitted which show that the MGA, lasalocid, tylosin combination is justified for its effect on estrus suppression, improved feed efficiency, increased rate of weight gain and reduction of liver abscesses. Each drug; MGA, lasalocid, and tylosin has been shown to make a significant (P<0.05) contribution to the effectiveness of the combination. The combination, when fed at up to 5X the highest recommended combination approval (0.5 mg MGA/head/day plus 30 g lasalocid/ton, and 10 g tylosin phosphate/ton for 90 days), did not produce an adverse effect. No changes were made in the approved levels of the compounds or in the target animal and the noninterference of tylosin phosphate, lasalocid sodium and MGA with the analytical methods for MGA, lasalocid sodium and tylosin phosphate, respectively, was demonstrated. Accordingly, approval of these NADA's is not expected to increase human exposure to drug resides, and therefore did not require a complete re-evaluation of the human safety data in the original applications. For the purposes of human food safety review, these original NADA's have been treated as Category II supplements under the Agency's Supplemental Policy (42 FR 64367). These production drugs are OTC because they do not raise any special safety concerns.

VIII. Labeling

  1. Type A Medicated Feed package label and mixing instructions
  2. Type B Medicated Feed package label and mixing instructions
  3. Type C Medicated Feed package label and mixing instructions

Copies of these labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855