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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 139-190 Baciferm; - Bio-Cox; - 3-Nitro - original approval

Approval Date: September 5, 1986

I. GENERAL INFORMATION:

NADA 139-190
Sponsor: International Minerals & Chemical Corporation
1401 South 3rd Street
P.O. Box 207
Terre Haute, IN 47808
Generic Name: bacitracin zinc - salinomycin sodium - roxarsone (3-nitro-4-hydroxyphenylarsonic acid)
Trade Name: Baciferm; - Bio-Cox; - 3-Nitro;
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 and improved feed efficiency.

III. DOSAGE

A. DOSAGE FORM

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

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

3-Nitro - 10, 20, 50 or 80% roxarsone

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.

Roxarsone (3-nitro-4-hydroxyphenylarsonic acid) at a concentration of 0.00375% (34.1 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" .

It has been established in approved NADA's that bacitracin zinc and roxarsone are both safe and effective for use in finished feeds for growing chickens and indicated for use to increase rate of gain and improve feed efficiency. This application contains data establishing that the action of each agent acts independently of the other (additive) to increase weight gain and improve feed efficiency while in the presence of salinomycin. These data demonstrate the safety and effectiveness of the combined use of bacitracin zinc-salinomycin-roxarsone when used in finished feeds containing bacitracin zinc 0.0011 to 0.0055% (10 to 50 g/ton) and salinomycin 0.0044 to 0.0066% (40 to 60 g/ton) and roxarsone 0.00375% (34.1 g/ton) for the prevention of coccidiosis in growing chickens caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti , and E. mivati and for increasing rate of gain and to improve feed efficiency. These data likewise demonstrate that bacitracin zinc does not interfere with the anticoccidial activity of salinomycin.

The approved salinomycin plus roxarsone NADA 132-447, established that the addition of roxarsone (3-nitro-4-hydroxyphenylarsonic acid) at a concentration of 0.005% to finished feeds containing salinomycin sodium between the range of 0.0044 to 0.0066% is safe and effective for the prevention of coccidiosis,in broiler chickens caused by E. necatrix, E. acervulina, E. brunetti , and E. mivati, including some field strains of E. tenella that are more susceptible to roxarsone combined with salinomycin than the salinomycin alone.

A. Summary of Drug Noninterference Studies

Two-week old, Hubbard x Hubbard, broiler chickens were used in adequate, well-controlled, 2-week, battery studies in a uniform environment with continuous artificial illumination to test for noninterference of bacitracin zinc with the effectiveness of salinomycin and roxarsone. 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 facilitated identification of lesions.

These studies (Tables I and II) were conducted by using the lowest approved level of salinomycin (40 g/ton) in the finished feed. 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 or roxarsone, 100 g/ton bacitracin zinc alone, 100 g/ton bacitracin zinc plus 45 g/ton roxarsone, and 40 g/ton salinomycin and 45 g/ton roxarsone plus 100 g/ton bacitracin zinc. The protocols were designed to show "noninterference", of each component with the others for the bacitracin zinc-salinomycin combination and the bacitracin zinc-salinomycin-roxarsone combination.

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

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

TABLE I  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
VI             Zinc Bacitracin +  100             0/40               1.2        1498b      1720c       1963b       5497b              880b              1.65b     1.62             4.5a                      
               Roxarsone           45
               Mixed
VII            Saliomycin +        40             0/40               0.4        1749a      2095b       2422a       6075a              937a              1.53b     1.53cd           1.0b
               Zinc Bacitracin +  100
               Roxarsone           45
               Mixed
VIII           Saliomycin +        40             0/40               0.3        1822a      2245ab       2560a      6068a              933a              1.49b     1.52cd           0.9b
               Roxarsone           45
               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       
VI             Zinc Bacitracin +  100             0/80                  0.5        0.4        2106        5029        1.60          1.65                3.62ab    1.62             4.5a                      
               Roxarsone           45
               Mixed
VII            Saliomycin +        40             0/80                  0.4        0.3        2147        5095        1.64          1.68                1.04c     1.53cd           1.0b
               Zinc Bacitracin +  100
               Roxarsone           45
               Mixed
VIII           Saliomycin +        40             0/80                  0.3        0.40       2123       5206         1.64          1.65                1.46c     1.52cd           0.9b
               Roxarsone           45
               Mixed

Note: Comparisons are based on Duncan's Multiple Range Test at the O.O5 levelbof significance. For a given column, any means not followed by the same letter are significantly different.

* Pen dropping scores assigned using a scale of 0 to 4 (Morehouse and Baron,b1970).

** Lesion scores assigned using a score of 0 to 4 (Johnson and Reid, 1970) for each area of the small intestine and ceca.

These studies demonstrate that there is "noninterference" of bacitracin zinc and/or roxarsone on the effectiveness of salinomycin. The combinations were 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 9600 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 zinc in the presence of salinomycin plus roxarsone. 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.

These studies were conducted as a 2 x 4 experimental design. Bacitracin zinc (0 and 50 g/ton) and roxarsone (0, 22.7, 34.1 and 45.4 g/ton) served as the two trial factors. Pens were randomly assigned to treatment within blocks; 50 to 60 birds, equally divided by sex, were selected at random and assigned to pens; 6 to 8 replicates were used per treatment group. Salinomycin, 60 g/ton (.0066%) was fed in the diet to all treatment groups. Studies were designed to simulate varying conditions, such as geographical locations, differences in climate, changes in weather, differences in management practices, and degree of disease contamination of the premises.

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

Birds medicated with the drug combinations were healthy throughout the study periods as evidenced by a survival rate of over 97% for all studies. There were no adverse drug toxicity effects observed.

A detailed examination of the 3 trials (Table III) was conducted. Data from the 3 studies were combined and an analysis of variance (weighted by 1ocation) conducted. Table IV defines the treatment groups and Tables V and VI gives the means for body weight and feed efficiency by location and averaged across locations by treatment group. The overall dose-titration analysis for weight gain showed a significant treatment difference in favor of bacitracin zinc (P=.0001), while the overall analysis for feed efficiency showed a marginally significant (P=.108) difference in favor of roxarsone. Linear plateau models were fit to the feed efficiency data to determine the optimum dose. The best fitting model showed no difference between levels 0 and 22.7, but a marked drop to a plateau beginning at leve1 34.2.

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

Table III Location and Design Study Information

 Trial    Study        Study          Pens/      Birds/
Location   No.      Investigator       Trt.       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 9 columns.)

Table IV Medication g/ton

                --------------------Treatment Group---------------------
Treatments       1      2       3       4      5      6       7       8
Roxarsone          0      22.7     34.1     45.4     0      22.7     34.1     45.4
Bacitracin Zn      0       0        0        0      50      50       50       50
Salinomycin       60      60       60       60      60      60       60       60

(Eds. note: The following table consists of 9 columns.)

Table V Mean Body Weight, Kg

                --------------------Treatment Group---------------------
Trial            1      2       3       4      5      6       7       8
C878             1.816   1.823    1.833    1.824   1.862   1.876    1.880    1.897
C880             1.513   1.536    1.585    1.595   1.582   1.591    1.704    1.634
C905             1.942   1.869    1.934    1.885   1.960   1.952    1.963    1.918
Average          1.757   1.743    1.784    1.768   1.801   1.806    1.849    1.816
Percent
Improvement      ---     0.0      1.5      0.6      2.5    2.8      5.2      3.4

(Eds. note: The following table consists of 9 columns.)

Table VI Feed Efficiency (F/G)*

                --------------------Treatment Group---------------------
Trial            1      2       3       4      5      6       7       8
C878             2.002   1.995    1.982    1.985   1.983   1.975    1.955    1.982
C880             2.016   1.951    1.909    1.861   1.866   1.864    1.728    1.754
C905             2.025   2.031    2.011    1.992   1.968   1.956    1.952    1.968
Average          2.014   1.992    1.967    1.946   1.939   1.932    1.878    1.901
Percent
Improvement      ---     1.1      2.3      3.4     3.7     4.1      6.7      5.6 
*F/G:  Feed consumed per body weight gain

The above data satisfy the requirements for approval under the CVM Policy outlined in the guidelines for combination drugs revised October, 1983. The policy provides for granting a range approval for production drugs in combination when the maximum level tested for the claim is demonstrated to make a significant benefit to the combination. The range approval for bacitracin zinc for weight gain, according to the revised policy, is from 50 g/ton to the minimum approved level for bacitracin zinc in the parent application of 4 g/ton. However, a minimum use level of 10 g/ton of bacitracin zinc was used in establishing the feed stability data for the combination. Accordingly, 10 g/ton of bacitracin zinc is the minimum approvable level. Linear-plateau models demonstrated that roxarsone for feed efficiency makes an optimal contribution at 34.1 g/ton. Thus the recommended use levels for this application are bacitracin zinc 10-50 g/ton plus 40-60 g/ton salinomycin, plus 34.1 g/ton roxarsone in broiler chicken rations.

The investigators were as follows:

Dr. Carey 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 salinomycin (NADA D-128-686), bacitracin zinc (NADA 46-920) and for roxarsone (NADA 7-891, MF-l9-roxarsone) contained adequate data to establish the safety of each drug for broiler chickens.

The safety of the combined use of the 3 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 both the battery and floor-pen studies receiving the drug combinations showed no signs of drug toxicity as evidenced by both gross necropsy examination, weight gain and/or feed efficiency data. Mortality data for each study was within an acceptable range, and there was no evidence of any toxicity which could be attributed to the combined use of the 3 drugs.

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 be fed to broiler chickens as indicated by the label.

These data provide evidence for the combination of bacitracin zinc 10-50 g/ton; salinomycin 40-60 g/ton; and roxarsone 34.1 g/ton in the feed of broiler chickens that is consistent with and fulfills all the requirements for a fixed combination drug for animals as follows:

  1. Each drug component makes a contribution to to the claimed effects.
  2. The dosage level of each drug component is such the combination is safe and effective for the purposes claimed.
  3. For a significant animal patient 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), salinomycin (Bio-Cox), and roxarsone (3-Nitro) -- has been established by data submitted in their respective original NADA's, NADA 46-920, NADA 128-686, and NADA 7-891 and Salsbury Master File 19.

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. Tolerances for residues of arsenic in the edible tissue of chickens are established at 0.5 ppm in muscle and 2 ppm in edible by-products (21 CFR 556.60).

B. Residue Depletion/Noninterference Studies

The residue data supporting the approved individual use of bacitracin zinc, salinomycin, and roxarsone and their established withdrawal times of zero, zero, and 5 days respectively, have been submitted in their respective applications (see Part A, above).

The following study, submitted by A.H. Robins under NADA's 137-536 and 135-746, establishes that the residues of each drug in the presence of the others is neither influenced nor exceed the established safe concentration or tolerance at their established withdrawal times, and that they do not interfere in each other's tissue residue assays.

One hundred broilers, one day old, were treated for 46 days with the three-way combination of salinomycin (80 g/ton), bacitracin zinc (100 g/ton), and roxarsone (45 g/ton). Tissues were collected and analyzed as shown in Table VII. From the residue data in Table VII both bacitracin zinc and roxarsone (as arsenic) are below their established tolerances of 0.5 ppm and 2 ppm at their established withdrawal times of zero and five days respectively. Under NADA 128-686, Robins Company established a research Rm, or tolerance, of 0.68 ppm for parent salinomycin in skin/fat. The residue data in Table VII for salinomycin confirms that, at zero withdrawal, the concentration of salinomycin is below the research Rm of 0.68 ppm and is similar to the value for salinomycin residues in skin/fat when salinomycin was used alone.

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

TABLE VII RESIDUE LEVELS OF SALINOMYCIN, BACTRACIN ZINC, AND ROXARSONE IN BROILERS

Drug - Tissue            Withdrawal (Days)       Concentration
Salinomycin - Skin/fat             0               29.4 ppb (SD=10.1, N=6)
Bacitracin - Muscle                0               (less than 0.3 ppm,N=6)
Arsenic - Liver                    0               1.60 ppm (SD=0.54, N=6)
                                   5               0.74 ppm (SD=0.22, N=6)

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 was no detectable assay interferences caused by salinomycin when assaying for bacitracin zinc in chicken muscle. Reference is made to Internationa1 Minerals & Chemical NADA P-136-484, that demonstrates that arsenic in the presence of bacitracin zinc in turkey muscle does not interfere with the bacitracin zinc assay.

These data support a 5-day withdrawal time for the bacitracin zinc-salinomycin-roxarsone combination.

A regulatory analytical method for salinomycin is not required. A practical analytical method for determination of tissue residue of bacitracin zinc and roxarsone is available in the Food Additives Analytical Manual on display in FDA's Freedom of Information Room (Room 12A-30), 5600 Fishers Lane, Rockville, MD 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 the combination of salinomycin, bacitracin zinc, with roxarsone given at the recommended dosage, according to the direction on the labeling is safe and effective for the prevention of coccidiosis, for increased rate of weight gain, and for improved feed efficiency in broiler chickens. Each of the active ingredients has been approved for use separately. The sponsor has demonstrated that each drug in the combination has depleted to or below its level of tolerance or safe concentrations following a 5-day withdrawal period.

This original NADA is regarded as a Category II application under CVM's supplemental policy (42 CFR 64367) which did not require reevaluation of safety and efficacy data in the parent NADA. The approval of this application will not significantly increase the exposure of consumers to residues of the drugs. The drugs in combination are safe to be fed to broiler chickens to be slaughtered for human consumption.

VIII. LABELING (Attached)

Copies of applicable labels 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.