• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Animal & Veterinary

  • Print
  • Share
  • E-mail

NADA 140-852 Monteban®, 3-Nitro®, BMD® - original approval

Approval Date: July 5, 1989

I. GENERAL INFORMATION:

NADA 140-852
Sponsor: A. L. Laboratories, Inc.
PO Box 1399
Fort Lee, New Jersey 07024
Generic Name: narasin, roxarsone, bacitracin methylene disalicylate
Trade Name: Monteban®, 3-Nitro®, BMD®
Marketing Status:  

 

II. INDICATIONS FOR USE

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

 

III. DOSAGE

A. DOSAGE FORM Narasin, roxarsone and bacitracin methylene disalicylate are marketed as separate Type A articles.
B. ROUTE OF ADMINISTRATION For oral administration via the feed for growing broiler chickens.
C. RECOMMENDED DOSAGES: Narasin: 54 - 72 grams/ton
Roxarsone: 22.7 - 45.4 grams/ton
Bacitracin methylene disalicylate: 10 - 50 grams/ton.
  NOTES For broiler chickens only. Feed continuously as sole ration. Withdraw 5 days before slaughter. Do not feed to laying hens. Use as sole source of organic arsenic. Drug overdose or lack of water may result in leg weakness. Do not allow adult turkeys, horses, or other equines access to feed containing narasin. Ingestion of narasin by these species has been fatal.

 

IV. EFFECTIVENESS

Non-Interference Study

A series of seven well controlled battery studies, using approved protocols and Hubbard white mountain broiler cockerels eight days of age raised under environmentally controlled conditions, was conducted to assure the non-interference of BMD and roxarsone on the anticoccidial efficacy of narasin. The chickens were challenged with six species of Eimeriaas individual infections and as a mixed infection of all six species. The studies were conducted at Lilly Research Laboratories, PO Box 708, Greenfield, IN 46140. Data from the mixed infection study are provided in this summary.

Experiment No. T 2N 8C AO-6

Investigator:

K.W. Bafundo, Ph.D. and J.D. Donovan
Greenfield Laboratories
PO Box 708
Greenfield, IN 40140

Monitor:

Ralph V. Fell, Ph.D.
Director, Technical Services
A.L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603

Each of 6 treatments (Table I) was replicated 4 times using 4 birds per replicate in 8 day old chicks in a coccidia free environment prior to the initiation of the experiment. Water and medicated feed were supplied ad libitum, proper ambient temperature and constant lighting schedules were maintained during the experiment.

A typical medicated broiler starter ration was provided for two days prior to the coccidial exposure and fed thereafter. Rations were assayed for BMD, roxarsone and narasin.

Forty-eight hours after initiation of medicated feeding the birds were inoculated with a mixed infective culture of E. tenella, E. necatrix, E. acervulina, E. maxima, E. mivatiand E. brunetti. Inoculum was intended to produce clinical coccidiosis in the infected non-medicated birds. The treatment regimen is set out below (Table I).

In six experiments inoculation was by single species challenge, i.e., one experiment for each of the six species of Eimeriaapproved for narasin. In the seventh experiment all six species were combined as the mixed inoculum.

Table I Treatments

  1. Infected, non-medicated controls
  2. Narasin (60 ppm)
  3. Narasin + BMD (60 + 110 ppm)
  4. Roxarsone (50 ppm)
  5. Narasin + Roxarsone (60 + 50 ppm)
  6. Narasin + BMD + Roxarsone (60+ 110 + 50 ppm)

Observations, measured by mortality, weight gain, feed conversion and lesion scores were conducted for 7 days post inoculum.

The data from these experiments are succinctly depicted in Tables II through Table VIII. The data show that neither the proposed level of BMD nor the proposed level of BMD + roxarsone interfered with the anticoccidial activity of the lowest approved level of narasin (54 grams/ton or 60 ppm).

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

Table II Summary of Experiment Eimeria maxima

Treatment       Dose   Mortality   Weight       Lesion Scores
               (ppm)      (%)       (g)     F/G   Intestine
Infected
Controls(1)        00        0.0        261.4    1.646     4.00
Narasin            60        0.0        291.4    1.552     0.38
Narasin +          60        0.0        283.6    1.517     0.31
BMD               110
Roxarsone          50        0.0        251.4    1.614     3.56
Narasin +          60        0.0        289.4    1.493     0.00
Roxarsone          50
Narasin +          60        0.0        271.6    1.554     0.00
BMD +             110
Roxarsone          50

(1) Chicks were infected with 50,000 Eimeria maximaoocysts.

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

Table III Summary of Experiment Eimeria necatrix

Treatment       Dose   Mortality   Weight       Lesion Scores
               (ppm)      (%)       (g)     F/G   Intestine
Infected
Controls(1)         0        0.0        222.3    1.779     3.50
Narasin            60        0.0        253.3    1.623     0.38
Narasin +          60        0.0        276.4    1.516     0.38
BMD               110
Roxarsone          50        0.0        243.8    1.676     3.13
Narasin +          60        0.0        271.9    1.507     0.25
Roxarsone          50
Narasin +          60        0.0        272.3    1.488     0.00
BMD +             110
Roxarsone          50

(1) Chicks were infected with 100,000 Eimeria necatrixoocysts.

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

Table IV Summary of Experiment Eimeria brunetti

Treatment       Dose   Mortality   Weight       Lesion Scores
               (ppm)      (%)       (g)     F/G   Intestine
Infected        
Controls(1)         0        0.0        176.9    2.155     4.00
Narasin            60        0.0        261.8    1.614     2.19
Narasin +          60        0.0        263.1    1.583     1.81
BMD               110
Roxarsone          50        0.0        215.0    1.894     3.88
Narasin +          60        0.0        293.4    1.447     0.44
Roxarsone          50
Narasin +          60        0.0        289.4    1.480     0.88
BMD +             110
Roxarsone          50

(1) Chicks were infected with 100,000 Eimeria brunettioocysts.

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

Table V Summary of Experiment Eimeria mitis/Eimeria mivati

Treatment       Dose   Mortality   Weight       Lesion Scores
               (ppm)      (%)       (g)     F/G   Intestine
Infected
Controls(1)         0        0.0        248.1    1.677     3.44
Narasin            60        0.0        276.2    1.547     1.25
Narasin +          60        0.0        286.0    1.455     0.69
BMD               110
Roxarsone          50        0.0        245.8    1.809     3.38
Narasin +          60        0.0        270.6    1.498     1.75
Roxarsone          50
Narasin +          60        0.0        281.8    1.474     0.81
BMD +             110
Roxarsone          50

(1) Chicks were infected with 100,000 Eimeria mitis/E. mivatioocysts.

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

Table VI Summary of Experiment Eimeria tenella

Treatment       Dose   Mortality   Weight       Lesion Scores
               (ppm)      (%)       (g)     F/G   Intestine
Infected 
Controls(1)         0        0.0        279.0    1.553     2.75
Narasin            60        0.0        272.0    1.521     1.69
Narasin +          60        0.0        293.6    1.507     0.44
BMD               110
Roxarsone          50        0.0        281.5    1.483     2.44
Narasin +          60        0.0        273.3    1.547     0.75
Roxarsone          50
Narasin +          60        0.0        284.6    1.469     0.38
BMD +             110
Roxarsone          50

(1) Chicks were infected with 100,000 Eimeria tenellaoocysts.

(Eds. note: The following table consists of 7 columns.)

Table VII Summary of Experiment Eimeria acervulina, E. maxima, E. mitis/mivati, E. brunetti, E. necatrix, and E. tenella

Treatment       Dose   Mortality   Weight           Lesion Scores
               (ppm)      (%)       (g)     F/G   Intestine   Cecal
               
Infected 
Controls(1)        0         0.0        199.8    1.846     8.94        1.13
Narasin           60         0.0        251.6    1.564     0.75        0.13
Narasin +         60         0.0        283.7    1.472     0.00        0.00
BMD              110
Roxarsone         50         0.0        201.1    1.844     8.44        1.88
            
Narasin +         60         0.0        273.3    1.477     0.25        0.00
Roxarsone         50
   
Narasin +         60         0.0        262.8    1.527     0.33        0.00
BMD +            110
Roxarsone         50

(1) Chicks were infected with a mixed inoculum Eimeria acervulina, E. maxima, E. mitis/mivati, E. brunetti, E. necatrixand E. tenellaoocysts.

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

Table VIII Feed Assay Results

Treat-                      --------Level (ppm)--------
ment No.  Treatment       T2N8C86AO-A2      T2N8C86A3-A6
                         Theory   Assay    Theory   Assay

   1         Narasin           0       0           0        0
   2         Narasin          60      53.95       60       55.45
   3         Narasin          60      53.85       60       58.45
   4         Narasin          60      53.55       60       57.10
   5         Narasin           0       0           0        0
   6         Narasin          60      54.15       60       56.75
   7         Narasin          60      52.15       60       55.80
   8         Narasin          60      53.15       60       55.35

   1         Roxarsone         0       0           0        0
   2         Roxarsone         0       0           0        0
   3         Roxarsone         0       0           0        0
   4         Roxarsone         0       0           0        0
   5         Roxarsone        50      44.0        50       47.0
   6         Roxarsone        50      44.0        50       47.5
   7         Roxarsone        50      47.0        50       46.5
   8         Roxarsone        50      42.5        50       47.0

   1         Bacitracin MD     0       0           0        0
   2         Bacitracin MD     0       0           0        0
   3         Bacitracin MD     0       0           0        0
   4         Bacitracin MD   110     111.4       110       90.6
   5         Bacitracin MD     0       0           0        0
   6         Bacitracin MD     0       0           0        0
   7         Bacitracin MD     0       0           0        0
   8         Bacitracin MD   110     109.7       110      124.9

These results show that narasin, both alone and in combination with roxarsone, effectively reduced lesion scores. The addition of BMD to feeds had no adverse effect on the ability of narasin or narasin + roxarsone to control coccidial infection. Thus BMD was found to be compatible with narasin or narasin + roxarsone when the drugs are fed to growing birds.

Floor Pen Trials

Six floor pen experiments were conducted using approved protocols and 10040 birds. BMD was used at 0 or 50 grams per ton of feed in combination with roxarsone at 0 or 45.4 grams per ton to provide the possible combinations of these two drugs. The anticoccidial narasin, at 72.5 grams per ton, was included in all treatments. The experiments were designed to confirm the effects of BMD and roxarsone in combination with narasin on body weight gain and feed efficiency.

Field Trial No. TX-B-146-86

Investigator:

Jack H. Trammel, Ph.D.
3T Research
Box 192
Hamilton, TX 76531

Monitor:

Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603

This 46 day trial was conducted in a conventional type dirt floor broiler house on the premises of 3T Research, Hamilton, TX during the period August 31 till October 17, 1980. The 28 pens in this trial are arranged in two rows with a center aisle. Each 5' x 10' pen is identically equipped with a cylindrical hanging self feeder, a Plasson automatic waterer and a thermostatically controlled gas brooder. Natural light is supplemented with electric bulbs down the center aisle. Built up litter was top dressed with new shavings after removal of wet spots. 30 males and 30 female birds per pen.

One thousand six hundred and eighty (1680) day old sexed chicks were randomly assigned into 28 experimental pens. Treatments were assigned to pens in a randomized block design. The 28 pens allowed for seven replications of the four treatments.

The experiment consisted of four dietary treatments: narasin at 72.5 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton; narasin 72.5 grams per ton + BMD 50 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton + BMD 50 grams per ton.

Industry mixing procedures were followed; feed samples were assayed for drug content.

Results:

  1. Increased rate of weight gain: The addition of BMD showed improved performance over narasin alone. Roxarsone in combination with BMD showed further advantage in weight gains.
  2. Feed conversion: The addition of roxarsone or BMD showed improved feed/gain over narasin alone. The combination of roxarsone, BMD and narasin showed even better improvement than the drugs used individually in combination with narasin.

Results are tabulated later in this summary.

Experiment No. TX-B-130-85

Investigator:

William F. Krueger, Ph.D.
Dept. of Poultry Science
Texas A & M University
College Station, TX 77843

Monitor:

Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603

This 2800 bird experiment was conducted in a conventional-type, dirt floor broiler house (Random Sample Broiler House 2) on the Texas A&M University Poultry Center. Vaccinated, day-old, sexed Hubbard x Hubbard broiler chicks were distributed randomly by sex into 28 pens so that each pen contained 50 males and 50 females, allowing 0.8 square foot of floor space per bird. Chicks that died during the first week were replaced with hatch mates. All mortality was recorded by date and pen after the initial replacement period.

Experimental diets were prepared by mixing the appropriate amount of each drug premix supplied by the sponsor with commercial-type starter and nutrient recommendations. Feed samples were assayed for drug content.

The 28 pens permitted 7 replications (pens) of the following 4 dietary treatments: narasin 72.5 grams per ton; narasin 72.5 grams per ton + roxarsone 45. 4 grams per ton; narasin 72.5 grams per ton + BMD 50 grams per ton; and narasin 72.5 grams per ton + roxarsone 45.4 g/t + BMD 50 grams per ton. Birds were on medicated feed for 46 days.

Results: A combination of narasin, BMD and roxarsone increased rate of gain significantly over birds fed narasin alone. Broilers receiving narasin + BMD or narasin + roxarsone were intermediate in weight at 46 days of age - heavier than birds receiving narasin alone but not as heavy as those receiving narasin + BMD + roxarsone combination.

Livability was not affected.

The above results are presented in tabulated form later in this summary.

Experiment No. MO-B-132A-85

Investigator:

Randall A. Primo
Ponderosa Research Co.
French Village, MO 63036

Monitor:

Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603

The 1200 experimental birds were housed in a conventional insulated, curtain-sided broiler house with wire partitions and dirt floor. Each 5' x 8' pen was identically equipped with an automatic water fountain, a cylindrical hanging self feeder and a heat lamp brooder. All feeders in each row are suspended from a common shaft so that all are raised and lowered together. Light to supplement natural daylight was supplied by a 25 watt bulb over the center of each pen. Built up litter was stirred and top dressed with new wood shavings after removal of caked or wet spots.

Day-old Arbor Acre x Peterson chicks were distributed randomly by sex into 24 pens so that each pen contained 25 male and 25 female chicks, with six replicates. For assignment of treatments to pens, the 24 pens were divided into blocks and dietary treatments assigned randomly within each block. Chicks that died during the first week were replaced with chicks from the same hatch. After the first week, all mortality was recorded by date and pen.

Experimental diets were prepared by blending the appropriate amount of the respective drug premixes supplied by the sponsor with commercial type starter and grower basal ration formulated to meet or exceed all NRC nutrient recommendations. The experiment entailed four dietary treatments: narasin 72.5 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton; narasin 72.5 grams per ton + BMD 50 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton + BMD 50 grams per ton. The experiment ran for 48 days.

Results: Narasin + BMD and narasin + BMD + roxarsone showed superior rate of gain over narasin alone or narasin + roxarsone.

Both narasin + BMD and narasin + BMD + roxarsone showed improved feed conversion over narasin alone or narasin + roxarsone.

Results are tabulated in full later in the summary.

Experiment No. MO-B-102-83

Investigator:

Randall A. Primo
Ponderosa Research Co.
French Village, MO 63036

Monitor:

Ralph V. Fell, Ph.D.
Director, Technical Services
A.L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603

The 1800 experimental birds were housed in a conventional, insulated, curtain-sided broiler house with wire partitions and dirt floor. Each 5' x 8' pen was identically equipped with an automatic water fountain, a cylindrical hanging self feeder and a heat lamp brooder. All feeders in each row are suspended from a common shaft so that all are raised and lowered together. Light to supplement natural daylight was supplied by a 25 watt bulb over the center of each pen. Built-up litter was stirred and top dressed with new wood shavings after removal of caked or wet spots.

Day-old sexed chicks of a popular broiler strain were randomly distributed by sex so that each pen contained 25 male and 25 female chicks. The 36 pens allotted to this study permitted 9 replications of each of the 4 dietary treatments as follows: narasin 72.5 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton; narasin 72.5 grams per ton + BMD 50 grams per ton; narasin 72.5 grams per ton + roxarsone 45 grams per ton + BMD 50 grams per ton.

Experimental diets were prepared by mixing the appropriate amount of each drug premix supplied by A.L. Laboratories with commercial-type starter and grower basal rations which were formulated to meet or exceed all National Research Council nutrient recommendations. Finished feeds were assayed for drug content.

The trial was terminated at 49 days of age by weighing by sex within each pen. A record of feed weight in and weight back was maintained. Chicks that died the first five days were replaced and a record of mortality was maintained thereafter.

Results: Narasin + BMD and narasin + BMD + roxarsone show superior rate of gain over narasin alone or narasin + roxarsone.

Both narasin + BMD and narasin + BMD + roxarsone showed improved feed conversion over narasin alone or narasin + roxarsone.

Results are tabulated in full later in this summary.

Experiment No. AR-B-119-84

Investigator:

Park W. Waldroup, Ph.D.
Department of Animal Science
University of Arkansas
Fayetteville, AR 72701

Monitor:

Ralph V. Fell, Ph.D.
Director, Technical Services
A. L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603

The 1440 experimental birds were housed in a conventional steel-truss building with insulated roof and sidewalls with a three-foot curtain. Pens are 7' x 8' and contained two hanging tube-type feeders, an automatic water fount and an infrared gas brooder. Plastic feeder flats and water founts were used during the first seven days for supplemental feeding and water. Wood shavings litter, used in a previous grow out, was stirred lightly and top dressed with new litter. Day-old, sexed broiler chicks obtained from a commercial hatchery were randomly distributed by sex into the pens so that each pen contained 30 males and 30 females. Male chicks had the toe web clipped for identification. Chicks that died during the first week were replaced with hatch mates.

Brooding temperatures began at 85°F with whole-house brooding with 5° per week reductions to a minimum of 65 degrees. Automatic fans and sidewall curtains were used to aid in maintaining temperature control.

The 24 pens allotted to this study permitted 6 replications of each of the 4 dietary treatments as follows: narasin 72.5 grams per ton; narasin 72.5 grams per ton + BMD 50 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton + BMD 50 grams per ton.

Finished feeds were assayed for drug content. Treatments were randomly assigned to pens within each of the 6 blocks of pens. The trial commenced April 2, 1984 and was terminated May 21, 1984 by weighing birds by sex within each pen.

Results: Narasin + BMD and narasin + BMD + roxarsone show superior rate of gain over narasin alone or narasin + roxarsone.

Both narasin + BMD and narasin + BMD + roxarsone showed improved feed conversion over narasin alone or narasin + roxarsone.

Results are tabulated in full later in this summary.

Experiment No. GA-B-131-85

Investigator:

O.W. Charles, Ph.D.
Extension Poultry Science
University of Georgia
Athens, GA 39601

Monitor:

Ralph V. Fell, Ph.D.
Director, Technical Services
A.L. Laboratories, Inc.
Route 9, Box 42
Pine Bluff, AR 71603

The 1120 bird, 49 day experiment was conducted in a conventional broiler house, Four Towers Research Center, University of Georgia from May 3, 1985 to June 21, 1985. Twenty-eight pens each containing 20 male and 20 female day-old Arbor Acre x Peterson chicks were allocated for this study. All pens were equipped with automatic circular bell-type waterers, a circular feeder and an electric heat bulb for brooding. Each pen received approximately 2 inches of new litter and top dressing was applied as necessary using new pine shavings. Medicated feeds were prepared as per standard industry practice. Finished feeds were assayed for drug content.

7 pens were assigned to each treatment group as follows: narasin 72.5 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton; narasin 72.5 grams per ton + BMD 50 grams per ton; narasin 72.5 grams per ton + roxarsone 45.4 grams per ton + BMD 50 grams per ton.

It should be noted that this trial was conducted during a period of excessively high temperatures. On several days, the temperature was in excess of 95°F; and in at least one instance, the temperature exceeded 100°F. The overall high livability and bird response is evidenced of good management practices in this experiment.

Results: The combination of both narasin + BMD and narasin + roxarsone + BMD were superior in increased rate of weight gain and in feed conversion as compared to narasin alone and narasin + roxarsone.

Results are tabulated in full later in this summary.

Summary of Floor Pen Studies

The six described floor-pen studies, using approved protocols and 10,040 broiler chickens (equal numbers of male and females) were conducted under conditions simulating actual field use to determine the growth promoting effects of BMD and roxarsone in combination with narasin. The studies were conducted in five different geographical locations.

Consistent with pen size and allowing 0.8 to 0.9 square feet per bird, 20 to 50 birds of each sex were selected at random and assigned to pens. Six to nine replicates were used per treatment group. BMD at 0 and 50 grams per ton of feed was used in combination with roxarsone at 0 or 45.4 grams per ton of feed to provide the possible combinations of these drugs. Narasin 72.5 grams per ton of feed was used in all feed in each study.

The studies were designed and conducted to simulate varying conditions as climate, geographical location, weather, management practices, and degree of disease contamination of the premises. Feed consumption was corrected for mortality by estimating feed consumed from standard tables based on age of each bird when it died in each pen and subtracting that amount from the total feed consumed by that pen.

A detailed statistical evaluation of the six studies was conducted by Dr. Charles Gates, Statistics Institute, Texas A&M University. The data were combined over the trials and analyzed using SAS's GLM Procedures*. Bacitracin methylene disalicylate at the 50 grams per ton level showed a significant effect as compared to narasin control for both feed efficiency and increased rate of weight gain. Roxarsone plus narasin was significantly superior to narasin alone for feed efficiency but not for body weight. Narasin plus roxarsone plus bacitracin methylene disalicylate was significantly superior to BMD plus narasin for increased rate of weight gain but not feed efficiency.

The results of specific treatment comparisons of data from the floor pen studies qualify this application for range approval for the three drug combination under CVM's drug combination policy revised October 1983. The data demonstrates that all three drugs contributed significantly to the effectiveness of the combination drug. These data permit CVM to grant approval for this application for the dosage levels and indications for use described in section two (II) of this document.

* (SAS User's Guide: Statistics, 1985 Edition, SAS Institute, Cary, NC)

 

V. ANIMAL SAFETY:

The basic animal safety data for bacitracin MD may be found in the parent NADA 46-592 sponsored by A.L. Laboratories, (approved March 15, 1976, 41 FR 10993); for narasin the data may be found in the parent NADA 118-980 sponsored by Elanco Products Co., (approved August 14, 1986, 51 FR 29098); for roxarsone the data may be found in the parent NADA 7-891, sponsored by Salsbury Laboratories (approved March 23, 1951). The efficacy studies shown in Section IV demonstrate that no adverse effects were observed when the drugs were combined, indicating that the drugs are as safe when fed in combination as when fed alone.

This application is in accord with the Animal Safety Guidelines. Additional safety studies were not required because: (1) The drugs have been approved singly and (2) adequate documentation has been provided to show that these compounds are compatible in combination when used in broiler chicken feeds. Therefore, based on the data in the original NADAs, the non-interference study, the floor-pen efficacy studies and the tissue residue depletion study, it is concluded that this combination of drugs may be safely fed to broiler chickens.

(Eds. note: The following table consists of 10 columns.)

Summary of Response of Broilers to BMD + Roxarsone + Narasin Fed in Combination

                                                                                   Narasin 72.5 g/ton +
                                       Narasin 72.5 g/ton +  Narasin 72.5 g/ton +  Roxarsone 45.4 g/ton +
                   Narasin 72.5 g/ton  Roxarsone 45.4 g/ton  BMD 50 g/ton          BMD 50 g/ton
    
                       Avg.  Feed/         Avg.  Feed/           Avg.  Feed/           Avg.  Feed/
           No. Reps    Wgt.  Gain          Wgt.  Gain            Wgt.  Gain            Wgt.  Gain
TX-B-146-86     7         4.33   1.94           4.35   1.94              4.41   1.91              4.55   1.96
TX-B-130-85     6         3.79   1.98           3.87   1.96              3.86   1.96              3.89   1.94
MO-B-132A-85    6         4.13   2.07           4.13   2.01              4.19   1.99              4.32   1.98
MO-B-102-83     9         4.28   2.20           4.30   2.13              4.47   2.03              4.46   2.10
AR-B-119-84     6         4.37   2.06           4.40   2.03              4.53   2.00              4.52   1.99
GA-B-131-85     7         3.95   2.05           3.94   2.03              4.05   2.00              4.16   1.97
Average                   4.14   2.05           4.16   2.00              4.25   1.98              4.31   1.97

 

VI. HUMAN FOOD SAFETY

A. Toxicity Tests

The data in the parent NADAs have demonstrated that these three drug products do not constitute a hazard to human health when used according to approved labeling. The basic safety data for bacitracin methylene disalicylate may be found in the parent NADA 46-592 sponsored by A. L. Laboratories, (approved March 15, 1976, 41 FR 10993); for narasin the data may be found in the parent NADA 118-980 sponsored by Elanco Products Co. (approved August 14, 1986, 51 FR 29098); for roxarsone the data may be found in the parent NADA 7-891, sponsored by Salsbury Laboratories (approved March 23, 1951).

B. Tolerances & Safe Concentration of Residues

The tolerance for residues of bacitracin methylene disalicylate (BMD) in uncooked tissues of chickens is established at 0.5 ppm negligible residue (21 CFR 556.70). Tolerances for residues of arsenic in edible tissues of chickens are established at 0.5 ppm in muscle and 2.0 ppm in edible by-products, (21 CFR 556.60). A tolerance for narasin residues in chickens is not needed, (21 CFR 556.428).

The safe concentrations for total narasin residues in uncooked edible tissues are: 0.6 ppm in muscle; 1.8 ppm in liver; 1.2 ppm in skin with adhering fat and fat. A tolerance refers to the concentration of marker residues in the target tissue used to monitor for total drug residues in the target animals. A safe concentration refers to the total residue concentration considered safe in edible tissues.

C. Tissue Residue Depletion Studies

A tissue residue study was conducted to demonstrate that there is no change in the residue depletion pattern of each drug when narasin, roxarsone and bacitracin methylene disalicylate were fed to broiler chickens in a three way combination. There were two segments to the study: (1) validation of the assay by assaying spiked tissue samples with the cited drugs, (2) assay for narasin, bacitracin methylene disalicylate and roxarsone were conducted on tissue samples harvested from medicated birds raised as in commercial production. Investigators: Dr. John A. Hebert, Louisiana State University; Randall A. Primo, Ponderosa Research Co., French Village, MO. Monitor: Dr. Ralph V. Fell, Director of Technical Services, A.L. Laboratories, Inc.

In two studies commercial broiler chicks 2-3 weeks of age equally divided as to sex were fed up to 7 weeks of age on diets containing (1) narasin 80 and 90 grams per ton, roxarsone 45.4 grams per ton, bacitracin methylene disalicylate 100 and 200 grams per ton, (2) unmedicated basal ration.

Tissues were collected from groups of 3M and 3F birds as follows:

For narasin assay: fat samples at 0, 1 and 2 days withdrawal.  

For roxarsone assay: liver, kidney, muscle and skin/fat at 0, 4 and 5 days withdrawal.

For bacitracin methylene disalicylate assay: muscle tissue at 0 and 2 days withdrawal.

Samples were labelled, quick frozen and shipped on dry ice to the respective laboratories for assay together with spiked control tissues for method validation. A summary of the tissue residue depletion studies are shown in Table I. These data confirm that each drug in the presence of the others does not exceed its approved safe concentration or tolerance. Therefore, these data support a five day withdrawal period for the use of this three way combination in broilers under CVM's combination drug policy.

D. Tissue Residue Non-Interference Studies

  1. Bacitracin Methylene Disalicylate Assay
    Tissue assay non-interference and method validation studies for bacitracin methylene disalicylate tissue assay were conducted by spiking control samples with bacitracin methylene disalicylate, roxarsone and narasin and then assaying for bacitracin methylene disalicylate residues. The assay results demonstrated no interference by narasin and roxarsone for bacitracin methylene disalicylate. (AL-TR-1-82).
  2. Narasin Assay
    A non-interference study, AAC-8855, for narasin was conducted by spiking control tissue samples with narasin, roxarsone and bacitracin methylene disalicylate and then assaying these tissues for narasin content. The results demonstrated no interference by bacitracin methylene disalicylate or roxarsone for narasin.
  3. Roxarsone Assay
    Assay non-interference data were not required for roxarsone due to the procedure for arsenic analysis.

E. Regulatory Methods

Bacitracin: Antibiotics Residue in Milk, Dairy Products and Animal Tissues: Methods, Reports, Protocols. National Center for Antibiotic and Insulin Analyses. Dept. HEW Washington, DC 20204, Rev. October 1968. Modified Method for Determination of Bacitracin in Tissues, Test Procedure Code 9A, A.L. Laboratories, Inc., One Executive Drive, PO Box 1399, Fort Lee, NJ 07024.

Narasin: Eli Lilly & Co., General Laboratory Procedure No. 7028. Sample Preparation for Microbiological Assay for Narasin in Raw Materials, Premixes and Animal Feeds. Eli Lilly & Co., General Laboratory Procedure No. 7016. Microbiological Assay for Narasin (Turbometric Method using S. faecium).

Arsenic: Assay Procedure No. 5801380 for chicken tissues essentially same as described in Office of Analysis of Association of Official Analytical Chemists, 11th Edition, p 402 (1970).

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

Table I Residue Depletion Assay Results

Tissue Residues        Liver     Kidney    Skin/Fat    Muscle
                        ----------------ppm----------------
Narasin
Established Safe
Total Residue              1.8         ---         1.2          .6
Narasin Residues:
0 day withdrawal           ---         ---         0.048(1)    ---
1 day withdrawal           ---         ---          NDR (2)    ---
2 day withdrawal           ---         ---          NDR (2)    ---
Roxarsone
Established Tolerances     2.0         2.0         2.0         0.5
Roxarsone Residues:
0 day withdrawal          1.90         0.43        0.2         0.16
1 day withdrawal          0.85         0.22        0.13        0.14
2 day withdrawal          0.69         0.15        0.10        0.11
Bacitracin Methylene Disalicylate
Established Tolerances    ---          ---         ---         0.5
BMD Residues:
0 day withdrawal          ---          ---         ---         0.40
2 day withdrawal          ---          ---         ---         0.43

(1) Represents 33% of the total narasin residue in skin/fat
(2) No detectable residues at a test sensitivity of 20 ppb.

 

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA satisfy the requirements of Section 512 of the Act and demonstrate that narasin (54-72 g/ton) plus roxarsone (22.7 -45.4 g/ton) plus bacitracin methylene disalicylate (10-50 g/ton) are safe and effective for the claims indicated in Section II of this FOI Summary.

This original NADA is regarded as a Category II application under CVM's supplemental policy, (42 FR 64367; December 23, 1977), which did not require reevaluation of safety and efficacy data in the parent NADAs. The drugs are to be fed in Type C medicated feeds, in accordance with Section II and III of this FOI Summary and the Blue Bird labeling that is attached to this document.

Residue depletion studies in this application demonstrate that residues of narasin at 0-day withdrawal will be below the safe concentration of 1.2 ppm in skin with adhering fat. The reported 0.048 ppm level of parent narasin in skin with adhering fat is well below its established safe concentration of 1.2 ppm in skin with adhering fat and is not appreciably different from the previously reported values for narasin alone.

Residues of bacitracin MD in edible tissues are below the tolerance of 0.5 ppm, established in 21 CFR 556.70. Residues of arsenic (from roxarsone) in edible tissues are below the tolerances of 2 ppm in uncooked edible by-products (by-products include liver) and 0.5 ppm in uncooked muscle tissue (21 CFR 556.60). Adequate information was submitted to demonstrate non-interference between the assays for each drug. The approval of this application will not significantly increase human exposure to drug residues.

Noninterference studies demonstrate that narasin in the presence of roxarsone and/or bacitracin MD prevented an outbreak of coccidiosis when the birds were exposed to the six major species of Eimeria. The data from six well-controlled floor pen studies demonstrate the effectiveness of bacitracin plus roxarsone for increased rate of weight gain and improved feed efficiency in broiler chickens in the presence of narasin. The policy outlined provides for the granting of range approval for narasin (54-72 g/ton) for the prevention of coccidiosis caused by Eimeria acervulina, E. brunetti, E. maxima, E. mivati, E. necatrixand E. tenella; for bacitracin MD (10 to 50 g/ton) and for roxarsone (22.7 to 45.4 g/ton) for increased rate of weight gain and improved feed efficiency in broiler chickens.

 

VIII. LABELING

  1. BLUE BIRD BROILER RATION TYPE C MEDICATED FEED package label

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

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