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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 139-235 Baciferm; - Bio-Cox - original approval

Approval Date: May 19, 1986

I. GENERAL INFORMATION:

NADA 139-235
Sponsor: International Minerals & Chemical Corporation
Generic Name: bacitracin zinc - salinomycin sodium
Trade Name: Baciferm; - Bio-Cox;
Marketing Status: Over the Counter (OTC)

II. INDICATIONS FOR USE:

For the prevention of coccidiosis in broiler chickens caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati; for increased rate of weight gain.

III. DOSAGE

A. DOSAGE FORM

Finished feeds manufactured from:

Baciferm - supplied as 10, 25, 40 and 50 grams of bacitracin zinc activity per pound of premix packaged in 50 lb bags.

Bio-Cox - 30 grams of salinomycin sodium per pound of premix.

B. ROUTE OF ADMINISTRATION Oral administration via the feed.
C. RECOMMENDED DOSAGES:

Bacitracin zinc (from Baciferm) at concentrations ranging from 0.0011% to 0.0055% (10-50 g/ton) in finished feed.

Salinomycin sodium (from Bio-Cox) at concentrations ranging from 0.0044% to 0.0066% (40-60 g/ton) in finished feed.

IV. EFFECTIVENESS

Animal Effectiveness

The salinomycin NADA (128-686) established that salinomycin 40 to 60 g/ton (0.0044 - 0.0066%) is a safe and effective aid "for the prevention of coccidiosis in broiler chickens caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati."

NADA 46-920 established the effectiveness of bacitracin zinc (from Baciferm) for use in broiler rations for increased rate of weight gain and improved feed efficiency. The present NADA (139-235) establishes that the addition of bacitracin zinc to rations containing salinomycin increased rate of weight gain. Data provided in this submission demonstrate that rations containing bacitracin zinc and salinomycin are effective when used at levels of 0.0011% to 0.0055% (10-50 g/ton) for bacitracin zinc and 0.0044% to 0.0066% (40-60 g/ton) salinomycin and are indicated for the prevention of coccidiosis in broiler chickens caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati; for increased rate of weight gain.

A. Summary of Drug Noninterference Studies

Two-week old, Hubbard x Hubbard, broiler chickens were used in adequate, well-controlled, 2-week, battery studies with approved protocols and were conducted in a uniform environment with continuous artificial illumination to test for noninterference of bacitracin zinc with the effectiveness of salinomycin. Recent field strain isolates collected from various broiler-producing regions of the United States were used. For each study, combinations of E. mivati, E. brunetti, and E. necatrix, or E. acervulina, E. maxima, and E. tenella were used. This arrangement facilitated identification of lesions.

These studies (Tables I and II) were conducted by using the lowest approved level of salinomycin (40 g/ton). The experimental treatment groups included uninfected unmedicated controls, infected unmedicated controls, infected groups receiving 40 g/ton of salinomycin with and without 100 g/ton bacitracin zinc, and 100 g/ton bacitracin zinc alone. the protocols were designed to test for "noninterference" of each component with the other for the bacitracin zinc-salinomycin combination.

In each of these studies, all pens were preselected, birds were randomized by weight and assigned to cages with 10 birds/cage with 4 replicates being used per treatment group. Medication was initiated 2 days prior to laboratory infection. Evaluations were by lesion scores (analysis was performed on preselected birds from each pen), dropping scores, weight gains, and feed conversions.

These studies demonstrate that there is "noninterference" of bacitracin zinc with the effectiveness of salinomycin. The combination was compatible.

The investigators were as follows:

Shi E. Cheng, D.V.M., Ph.D.
A. H. Robins Co., Inc.
1405 Cummings Drive
P. O. Box 26609
Richmond, VA 23261-6609

Michael D. Sims, B.S.
A. H. Robins Co., Inc.
1405 Cummings Drive
P. O. Box 26609
Richmond, VA 23261-6609

Patricia C. Gerber, A.A.S.
A. H. Robins Co., Inc.
1405 Cummings Drive
P. O. Box 26609
Richmond, VA 23261-6609

B. Floor-Pen Studies

Three adequate and well-controlled floor-pen studies using approximately 3312 broiler chickens (equal number of male and female), were conducted under simulated actual use to determine the growth promoting and feed efficiency effects of bacitracin

(Eds. note: The following table consists of 13 columns.)

TABLE 1  Anticocicdial Activity of Salinomycin and Salinomycin in Combinationion withZinc Bacitration Against a mixed Eimeria Infection in 2-Week-Old Chicks Experiment 84-034  

                                                          Average       
                                        Coccidiosis-      Dropping    -----------Weight Gain (g)----------       Average Live-       Feed Conversion   
Treatment    Medication                   Induced          Score*                                                Bird Weight                             Total Lesion  
Group        Infection       g/ton       Mortality         D4-D8      Day 5     Day 6     Day 7     Day 14        on Day 14          Day 7   Day 14        Scores** 
                                                                                                                 
           
  
I              None                 0             0/40               0.O        1803a      2227ab      2525a       6131a              944a              1.44b     1.45d            0.0c           
               Uninfected
                 
II             None                 0             8/40               2.4         879d       559d        533c       3750c              702c              2.77a     2.10a            5.7a       
               Mixed  
                 
III            Salincomycin        40             0/40               0.5        1880a      2214ab      2637a       6309a              958a              1.52b     1.52cd           1.3b     
               Mixed  
                 
IV             Zinc Bacitracin    100             5/40               2.0        1083c       769d        746c       3950c              733c              2.57a     1.93b            5.2a     
               Mixed  
V              Saliomycin +        40             0/40               0.6        1918a      2390a       2625a       6320a              957a              1.5lb     1.50cd           0.9b         
               Zinc Bacitracin    100
               Mixed
                 
NOTE: Comparisons are based on Duncan's Multiple Range Test at the 0.05 level of
      significance. For a given column, any means not followed by the same letter are
      siginficantly different.  
  
*  Pen dropping scores assigned using a scale of 0 to 4 (Morehouse and Baron,
   1970).  
  
** Lesion scores assigned using a score of O to 4 (Johnson and Reid, 1917) for
   each area of the small intestine and ceca 
   
 

(Eds. note: The following table consists of 11 columns.)

Table II  Anticoccidial Activity of Salinomycin and Salinomycin in Combination with Zinc Bacitracin Against a Mixed Eimeria Infection in 2-Week-Old Chicks (Pooled Studies 84-035 and 84-110) 

                                                             Average Dropping
                                                                  Score*    
                                        Coccidiosis-         -----D4-D8------      Weight Gain (g)       Feed Conversion
Treatment    Medication                   Induced                                                                                    Total       
Group        Infection       g/ton       Mortality           84-035    84-110     Day 7     Day 14     Day 7     Day 14 (g)     Lesion Scores**
                                                                                                                
                     
      
I              None                 O             0/80                  O.O         0         2236        5138        1.50          1.55                O.OOd          
               Uninfected       
       
II             None                 0            11/80                  1.1        1.7        1698        4902        1.91          1.79                5.62a        
               Mixed       
       
III            Salinomycin         40             3/80                  O.7        1.6        1876        4793        1.79          1.71                2.08bc       
               Mixed       
       
IV             Zinc Bacitracin    100            10/80                  1.3        2.1        1700        4737        1.82          1.75                5.46a    
               Mixed   
    
V              Salinomycin +       40             3/80                  0.9        1.5        1740        4891        1.84          1.71                2.21bc    
               Zinc Bacitracin
               Mixed       
    
Note:  Comparisons are based on Duncan's Multiple Range Test at the O.O5 level of significance.  For a given column, any means not followed by the sameletter are significantly different.    
*  Pen dropping scores assigned using a scale of 0 to 4 (Morehouse and Baron, 1970).       
** Lesion scores assigned using a score of 0 to 4 (Johnson and Reid, 1970) for each area of the small intestine and ceca.

(cont'd) zinc in the presence of salinomycin. All diets were balanced to provide adequate levels of nutrients (protein, energy, minerals, etc.). The same general experimental design was used in all studies. All chickens were maintained from one day of age to market weight. The studies were conducted in 3 geographical areas.

In these studies, pens were randomly assigned to treatment within blocks, 50-60 birds (one-half male; one-half female) were selected at random and assigned to pens; 6-8 replicates were used per treatment group. Salinomycin at 60 g/ton (.0066%) and bacitracin zinc at 0, and 50 g/ton was used on all studies. Studies were designed to simulate varying conditions, to include geographical locations, differences in climate, changes in weather, differences in management practices, and degree of disease contamination of the premises.

Data were collected of the evaluation of bacitracin zinc for increasing rate of weight gain and improving feed efficiency in the presence of the highest recommended approved use level of the anticoccidial drug (salinomycin, .0066%). Parameters of evaluation included mortality, body weight gain and feed to body weight gain ratio.

Birds medicated with the combinations were healthy throughout the study periods as evidenced by a survival rate of over 98% for all studies. There were no adverse drug effects observed.

A detailed statistical examination of the 3 studies was conducted. Data were combined over 3 locations and an analysis of variance (weighted by location) conducted according to block design, and mean differences separated using the least significant difference test (P<.05). The combined analysis of variances demonstrated significant bacitracin effects, i.e., that the 50 g/ton treatment was significantly better for increased rate of weight gain (P<.01), while in the presence of salinomycin. The combined individual treatment means (Table IV and V) illustrates the responses from the combination.

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

Table III Location and Design Study Information  

Trial Location   Study No.    Study Investigator      Pens/Trt.     Birds/Pen 
 Colorado          C878        Dr. C.L. Quarles         6             50  
 Oklahoma          C880        Dr. R.G. Teeter          8            50-60  
 Georgia           C905        Dr. R.B. Davis           8             58

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

Table IV Mean Body Weight, Kg

Trial       Treatments in the Presence of 60 g/ton Salinomycin                   
                        0 g/ton             50 g/ton  
                    Bacitracin Zinc     Bacitracin Zinc  
   
 C878                        1.816                 1.862  
   
 C880                        1.513                 1.582  
   
 C905                        1.942                 1.960  
   
 
 Average                     1.757                 1.801  
   
 Percent  
 Improvement                   --                  2.5

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

Table V  Feed Efficiency (F/G)*  

             Treatments in the Presence of 60 g/ton Salinomycin  
   
                        0 g/ton             50 g/ton
 Trial              Bacitracin Zinc     Bacitracin Zinc
   
 C878                        2.002                 1.983  
   
 C880                        2.016                 1.866  
   
 C905                        2.025                 1.968  
   
 
 Average                     2.014                 1.939  
   
 Percent   
 Improvement                   --                  3.7  
   
 *F/G:  Feed consumed per body weight gain

These studies demonstrate that there is "non-interference" of bacitracin zinc with the effectiveness of salinomycin. Bacitracin zinc is compatible with salinomycin.

The above data satisfy the requirement for evaluation of an application under the CVM Policy outlined in the guidelines for combination drugs revised October 1983. The policy provides for the granting of a range approval for production drugs in combination when the maximum level tested for the claim(s) is demonstrated to make a significant benefit to the combination. The range approval according to the revised policy is from 50 g/ton to the minimum level approved for bacitracin zinc in the parent application. A minimum use level of 10 g/ton was used in establishing the feed stability data for this combination. Accordingly, 10 g/ton of bacitracin zinc is the minimum approvable level. Therefore, use levels approvable for this application are 10-50 g/ton of bacitracin zinc and 40-60 g/ton of salinomycin in broiler rations.

The investigators were as follows:

Dr. Cary L. Quarles
Colorado Quality Research, Inc.
2629 Redwing Road
Creekside Two, Suite 315
Fort Collins, Colorado 80526

Dr. Robert G. Teeter
Department of Animal Science
Oklahoma State University
Stillwater, Oklahoma 74078

Dr. Richard B. Davis
4785 Lexington Road
Athens, Georgia 30605

V. ANIMAL SAFETY

The original approved NADA's for bacitracin zinc (NADA 46-920) and salinomycin (NADA 128-686) contained adequate data to establish the safety of each drug for broiler chickens.

The safety of a combination of the 2 drugs was demonstrated in the drug residue elimination study, the floor-pen studies and the compatibility battery studies described in this document. Birds in the drug elimination studies were in good health throughout the study and did not have any gross pathology at sacrifice. The birds in the floor-pen and battery studies were healthy throughout the experimental periods. Mortality in each study was within an acceptable range for each facility, and there was no evidence that drug was the cause of any death.

Based on the data in the parent NADAs, the compatibility battery studies, the drug elimination residue study, and the floor-pen studies, we conclude that the combination is safe to be fed to broiler chickens as indicated by the label.

The data provide evidence for the combination of bacitracin zinc 10-50 g/ton and salinomycin at 40-60 g/ton in the feed of broiler chickens that is consistent with and fulfills all the requirements for a combination drug for animals as follows:

  1. Each drug component makes a contribution to the claimed effects.
  2. The dosage of each drug component are such that the combination is safe and effective.
  3. For a significant animal population that is affected by a significant disease condition, Eimeria tenella is a major and widespread etiological organism for coccidiosis and the most pathogenic Eimeria species for chickens and, as such, possess the potential of causing extensive economic losses to broiler producers.
  4. The label claims are not antagonistic.

VI. HUMAN SAFETY

A. Data to Support Human Safety
Safety for the approved products -- bacitracin zinc (Baciferm) and salinomycin (Bio-Cox)--has been established by data previously submitted in their respective parent NADA's, NADA 46-920, and NADA 128-686. Tolerances for residues of bacitracin zinc in edible tissue of chickens is established at 0.5 ppm (21 CFR Section 556.70). Safe concentrations of salinomycin in the edible tissues of chickens are 0.6 ppm for muscle, 1.8 ppm for liver and 1.2 ppm for skin/fat.

B. Residue Depletion/Non-Interference Studies

The residue data supporting the approved individual uses of bacitracin zinc and salinomycin and their withdrawal times of zero and zero, respectively, have been submitted in their respective parent applications (see Part A, above).

The studies indicated below establish that each drug in the presence of the other does not influence or exceed the established safe concentration or tolerance at withdrawal and that they do not interfere in each other's tissue residue assays. Residue depletion studies conducted on the three-way combination of salinomycin, roxarsone, and bacitracin were used to support the two way combination of salinomycin and bacitracin zinc.

Under NADA 128-686, a research Rm was established for salinomycin from birds dosed with salinomycin only.

Unchanged 14C-Salinomycin was determined by TLC/radiotracer. After 6 hours withdrawal, unchanged salinomycin was 0.035 ppm in skin/fat with total salinomycin residues of 0.061 ppm. Using skin/fat as the target tissue, a ratio of parent drug to total, residue of 0.57 was calculated at zero withdrawal. Thus, the permissible level of unchanged salinomycin (marker) in skin/fat at zero withdrawal would be equal to the product of the ratio value and the safe concentration (1.2 ppm) or 0.68 ppm.

Under NADA 135-746, broilers were dosed for 46 days with the three-way combination of salinomycin (80 g/ton) /roxarsone (45 g/ton) /bacitracin zinc (100 g/ton). Six birds were sacrificed at zero withdrawal and skin/fat collected for determination of salinomycin using a microbiological assay. The average salinomycin concentration in skin/fat at zero withdrawal was found to be 29.4 ppb +/- 10.1. Thus, the concentration of parent salinomycin is approximately equal to that found in NADA 128-686 and is below the research Rm of 0.68 ppm.

Another drug residue elimination study was completed under protocol 84-039 at the A. H. Robins facility in Ashland, Virginia, examining bacitracin zinc while in the presence of salinomycin and roxarsone. A total of 30 birds was reared for control tissue (no drug) and another 30 broilers received the combination of 0.0088% salinomycin plus. 0.011% bacitracin zinc from day 0 to day 41. On day 41 (zero withdrawal) six birds (3 males, 3 females) were sacrificed from the above combination treatment group and assayed for bacitracin zinc residue. Edible tissue assayed was muscle. There was no bacitracin zinc residue found in any of the muscle tissue at zero day withdrawal.

Reference is also made to A. H. Robin NADA P-137-536, which indicates that spiking of muscle homogenate with various combinations of salinomycin and bacitracin zinc do not affect the size of salinomycin inhibition zones. Therefore, bacitracin zinc does not interfere with the salinomycin assays.

A non-interference study for bacitracin zinc was conducted by spiking control muscle tissue with 0.5 ppm bacitracin zinc and 80 ppb of salinomycin. There were no detectable assay interferences caused by salinomycin when assaying for bacitracin zinc in chicken muscle.

A regulatory analystical method for salinomycin is not required. A practical analytical method for the determination of tissue residue of bacitracin zinc is available in the Food Additives Analytical Manual on display in FDA's Freedom of Information Room (Room 12A-30), 5600 Fishers Lane, Rockville, Maryland 20857.

VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA comply with the requirements of Section 512 of the Act and demonstrate that salinomycin (40-60 g/ton) plus bacitracin zinc (10-50 g/ton) are safe and effective for the claims indicated in Section III of this FOI Summary.

Residue depletion studies demonstrating that salinomycin depletes to safe concentration and bacitracin zinc depletes below tolerance (0.5 ppm) at zero withdrawal are summarized in this application.

Under the Center's supplemental policy (42 FR 64367) this original application is regarded as a Category II supplemental NADA which did not require reevaluation of safety and efficacy data in the parent NADA's. The drugs are to be fed in medicated feeds under the same indications and dosages as approved in the parent NADA's.

Non-interference studies demonstrate that salinomycin plus bacitracin zinc pre ented an outbreak of coccidiosis when the birds were exposed to six major Eimeria species that cause the disease. The data from three well-controlled floor pen studies demonstrate the effectiveness of bacitracin zinc (50 g/ton) to increase rate of weight gain in the presence of salinomycin (60 g/ton). The CVM policy outlined in the combination drug efficacy guidelines revised October 1983, permits the granting of range approval for bacitracin zinc of 10 to 50 g/ton for increased rate of weight gain in combination with salinomycin 40 to 60 g/ton for the prevention of coccidiosis caused by six major Eimeria species.

VII. LABELING(Attached)

  1. Bag label

Copies of this label may be obtained by writing to the:

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857

Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.