Approval Date: March 4, 1985
Freedom of Information Summary
NADA 098-341
I. GENERAL INFORMATION:
NADA 098-341 Sponsor: American Hoechst Corporation, Animal Health Division
Animal Health Division
Route 202-206 North
Somerville, NJ 08876Generic Name: bambermycins, roxarsone, monensin Trade Name: Flavomycin®, 3-Nitro, Coban Marketing Status: II. INDICATIONS FOR USE
III. DOSAGE
For the prevention of coccidiosis caused by E. tenella, E. necatrix, E. acervulina, E. maxima, E. mivati, E. brunetti;
For increased rate of weight gain in broiler chickens.
IV. EFFECTIVENESS
A. DOSAGE FORM Bambermycins, roxarsone and monensin are marketed as separate feed additive premixes.
The bambermycins premix is sold in two concentrations: 10 and 2 g bambermycins activity per pound.
Roxarsone premix is sold in three concentrations: 10, 20, and 50% medicated premix.
Monensin premix is sold in concentrations of 45 grams and 110 grams of monensin activity per pound.
B. ROUTE OF ADMINISTRATION oral via the feed C. RECOMMENDED DOSAGES: Bambermycin (1 to 2 g/ton) Bambermycins is mixed into finished broiler feed at concentrations ranging from 1 to 2 g/ton for increased rate of weight gain. Roxarsone 22.7 to 45.4 g/ton Roxarsone is added to finished broiler feed at a concentration of 0.0025 to 0.005% for increased rate of weight gain. Monensin 90 to 110 g/ton Monensin is added to finished broiler feed at a concentration of 90-110 g/ton for the prevention of coccidiosis caused by E. tenella, E. necatrix, E. acervulina, E. maxima, E. mivati, and E. brunetti. NOTES Feeds containing roxarsone must be withdrawn from broilers 5 days before slaughter. Feeds containing monensin must be withdrawn from broilers 3 days before slaughter. A. Floor Pen Studies - Body Weight:
The New Animal Drug Application on which approval of bambermycins and roxarsone in combination with monensin is based contains adequate and well-controlled studies demonstrating the effectiveness of bamber-mycins, roxarsone, and monensin when fed to broilers. Four experiments using a 4 x 4 factorial in a randomized complete block design were conducted utilizing 11,440 broilers which were fed from one (1) day of age to market weight. These experiments were summarized and evaluated for significant differences in average live bird weight.
In these four studies, pens were randomly assigned to treatments within blocks; 20 to 100 birds of equal sex were selected at random and assigned to each pen; 3 to 4 replicates were used per treatment group. In these experiments, the drug premixes were fed at the following levels:
Monensin - 110 g/ton
Bambermycins - 0, 1, 2 and 4 ppm
Roxarsone - 0, 0.0025, 0.00375, and 0.005%The summary was done using only the combination of treatments necessary under the revised guidelines for broiler combination efficacy studies (Guideline for Drug Combinations for use in Animals, Center for Veterinary Medicine, October 1983). Thus, only the following treatments from each of the four studies were pooled and subjected to statistical analysis:
Monensin - 110.0 g/t.
Bambermycins - 2.0 g/ton + Monensin 110 g/ton.
Roxarsone - 45.4 g/ton + Monensin 110 g/ton.
Monensin - 110 g/ton + Bambermycin 2 g/ton + Roxarsone 45.4 g/ton.
Studies were designed to simulate varying conditions such as geographical location, differences in climate, changes in weather, differences in management practices, and degree of disease contamination of the premises. The chicks were grown on old litter and diets were balanced to provide adequate levels of all nutrients.
The effect of bambermycins and roxarsone on average live bird weight is presented in Table I.
An analysis of the combined data shows an overall significant (P<.05) response in average live bird weight due to feeding bambermycins or roxarsone with monensin. Further analysis of the combined data shows that when monensin, roxarsone and bambermycins are combined, a significant (P<.05) additive increase in body weight is seen over feeding the products separately. Therefore, based on the revised Drug Combination Guidelines, these data are adequate for the claims shown on Page 1, Item 2, under Indications of Use.
Ed. note: The following table has seven columns.
TABLE I Body Weight (pounds) Treatments± _____________________________________________ Bambermycins (2.0 ppm) Pens Per Birds Roxarsone Bambermycins Roxarsone Study Location Treatment Per Pen Control (0.005%) (2.0ppm) (0.005%) Colorado 4 50 3.77 3.77 3.85 3.88 Florida 4 20 3.85 3.92 3.85 4.01 Mississippi 3 50 3.74 3.95 3.79 4.00 Arkansas 3 100 3.72 3.75 3.85 3.93 Average 3.77 3.84 3.84 3.95Bambermycins - 1.0 to 2.0 g/t of complete broiler feed.
Roxarsone - 0.0025 to 0.005% of complete broiler feed.
Monensin - 90.0 to l10.0 g/t of complete broiler feed.
Bambermycins, roxarsone and monensin have all been approved singly in three separate NADA's for addition to complete broiler feed at the above rates.
The above studies were conducted by the following;
Dr. Carey L. Quarles
Animal Sciences Dept.
Colorado State University
Ft. Collins, CO 80523Dr. Ben C. Dilworth
Poultry Science Dept.
Mississippi State University
Mississippi State, MS 39762Dr. James Whitmore
403 Maple Ave.
Springdale, AR 72764Dr. R. H. Harms
Dept. of Poultry Science
University of Florida
Gainesville, FL 32601B. Noninterference Battery Study
Seven-day old broiler chickens were used in an adequate, well-controlled battery study to test for the noninterference of bambermycins and roxarsone on the anticoccidial efficacy of monensin.
Recent field strain isolates of coccidia were used.
Combinations of E. acervulina, E. maxima, E. tenella, E. brunetti, E. necatrix, and E. mivati were used. This arrangement facilitated identification of lesions.
Tables II-VI show the treatments used in this battery study along with the results for body weight, feed efficiency, lesion scores, and mortality. The broilers were randomized and assigned to cages with 5 broilers per cage. There were six (6) replicates of each treatment group.
This battery study adequately demonstrates that there is noninterference of bambermycins and roxarsone on the anticoccidial efficacy of monensin. Therefore, this combination is compatible.
The investigator involved in the above battery study was:
Dr. Maurice Callender
Eli Lilly & Co.
Greenfield Laboratories
Greenfield, IN 46140V. ANIMAL SAFETY
The original NADA's contain complete information on the animal safety of all three products (NADA's 44-759 - bambermycins, 38-878 and 41-500 - monensin, 7-891-MF19 - roxarsone). The above effectiveness (Section 4) studies adequately demonstrated that there were no toxicological or pharmacological effects when the three drugs were combined in the same feed. No reactions were expected or found when the three drugs were combined indicating that they are equally safe when fed separately or when combined.
This application is in accord with Animal Safety Guidelines. Further safety studies were not required because:
a. The drugs have been approved singly; and
b. Sufficient documentation has been provided to determine that these compounds are compatible in combination when used in poultry.
Based on the data in the parent NADA's, the compatibility battery studies, the drug residue elimination study, and the floor pen efficacy studies, we conclude that the combination of these three drugs is safe to be fed to broiler chickens as indicated by the label.
Table II. %Mortality - Infected Birds Monensin Roxarsone Flavomycin® %Conc. % Conc. %Conc. %Mortality* 0 0 0 66.7(c) 0 0.005 0.00044 30(b) 0.0121 0 0 0(a) 0.0121 0.005 0 3.3(a) 0.0121 0.005 0.00044 0(a) * Due to coccidiosis Table III. Mean Weight Gain (g) Surviving Birds Monensin Roxarsone Flavomycin® Mean % Conc. % Conc. % Conc. Weight Gain 0 0 0 62(a) 0 0.005 0.00044 87(a) O.O121 0 0 172(bc) O.O121 0.005 0 167(b) O.0121 0.005 0.00044 168(b) Noninfected, nontreated controls 198(c) Means with the superscript letter did not differ significantly (P<.05). Table IV. Feed/Gain Monensin Roxarsone Flavomycin® Mean % Conc. % Conc. % Conc. Weight Gain 0 0 0 * 0 0.005 0.00044 2.44(c) O.O121 0 0 1.67(b) O.O121 0.005 0 1.66(b) O.0121 0.005 0.00044 1.66(b) Noninfected, nontreated controls 1.50(a) *Not calculable due to mortality in all replicates.Table V.
Intestinal Lesion Score Monensin Roxarsone Flavomycin® Total Instestinal % Conc. % Conc. % Conc. Lesion Score 0 0 0 4.10(b)* 0 0.005 0.00044 4.00(b)* O.O121 0 0 0.47(a) O.O121 0.005 0 0.17(a) O.0121 0.005 0.00044 0.10(a) * Each of the intestinal species prescnt in the inoculum confirmed by phase contrast microscopy of intestinal lesions at necropsy. Table VI. Cecal Lesion Scores Monensin Roxarsone Flavomycin® Cecal % Conc. % Conc. % Conc. Lesion Score 0 0 0 3.50(b) 0 0.005 0.00044 3.50(b) O.O121 0 0 0.63(a) O.O121 0.005 0 0.43(a) O.0121 0.005 0.00044 0.40(a) The following summary of a safety growth study demonstrates normal growth with no incidence of disease or other abnormalities when the three drugs were fed at the highest approved use levels.
A SAFETY GROWTH STUDY
Investigator:
Dr. Ben C. Dilworth
Poultry Science Dept.
Mississippi State University
Mississippi State, MS 39762The following table shows that the broilers grew well and feed efficiency was not adversely affected by any of the treatments. After this data was collected, the broilers were sacrificed and tissues were collected. The results of the tissue assays for drug residues are presented in Section 6 (Human Safety).
TABLE VII - SAFETY STUDY SUMMARY - EIGHT WEEK DATA Broiler Final Body Final Feed Treatment Drug Level Number Wt. (lbs) Efficiency Control --- 150 3.73 2.17 Monensin 110 g/T Bambermycins 4 ppm 150 3.88 2.11 Monensin 110 g/T Bambermycins 4 ppm Roxarsone 0.005% 150 4.12 2.07The data provide evidence for the combination of monensin, bambermycins, and roxarsone in the feed of broiler chickens and these data are consistent with and fulfill all the requirements for a fixed combination drug for animals as follows:
a.Each drug component makes a contribution to the claimed effects.
b.The dosages of each drug component are such that the combination is safe and effective.
c.This combination demonstrates significant control of a specific disease condition for a large patient animal population. Specifically, Eimeria tenella is a major widespread organism of coccidiosis and the most pathogenic Eimeria species and, as such, possesses the potential of causing extensive economic losses to broiler producers.
d. The label claims are not antagonistic.
VI. HUMAN SAFETY:
The original NADA's for each drug (44-759, bambermycins; 38-878 and 41-500, monensin; 7-891-MF19, roxarsone) demonstrate that these products do not cause a hazard to human health when used according to label directions.
Tolerances of arsenic (from roxarsone) in the edible tissues of chickens are established at 0.5 ppm in muscle and 2 ppm in edible by-products (21 CFR 556.60). Bambermycins has a no tolerance clearance (safe concentration) as published in the Federal Register, Vol. 40, No. 250, page 59726 on 12/30/75. Tolerances of monensin in edible tissues of chickens have been established at 0.05 ppm (21 CFR 556.420).
The residue data supporting the approved individual uses of monensin, bambermycins, and roxarsone and their respective withdrawal times of 3, 0, and 5 days have been submitted in their respective original applications. The summary of the study presented in Table VIII establishes that each drug in the presence of the other does not exceed its established safe concentration or tolerances at 0, 3, or 5 days withdrawal and they do not interfere in each other's tissue residue assay. Table VIII summarizes the data obtained from a study in which 300 broilers were fed the combination of monensin (110 g/T), bambermycins (4 ppm), and roxarsone (0.005%) for 56 days. Edible tissues, including liver, kidney, muscle, and skin/fat were assayed for drug residues. The edible tissues were collected on the withdrawal dates indicated in Table VIII.
Along with the residue depletion results presented in Table VIII, a noninterference study for the bambermycins tissue assay was conducted by spiking samples with bambermycins plus monensin and roxarsone and conducting assays for bambermycins residues. The results demonstrated no interference by monensin and roxarsone on the assay for bambermycins.
TABLE VIII
RESIDUE DEPLETION STUDY ASSAY RESULTs (PPM)
Withdrawal Tissue* Drug Day Assay Kidney Liver Skin/Fat Muscle Bambermycins 0 ND** ND ND ND Monensin 0 <.05(0.0) <.05(0.0) <.05(0.0) <.05(0.0) Roxarsone 5 0.93(0.07) 0.95(0.37) 0.33(0.03) 0.19(0.02) *Average of 6 birds; standard deviation in parentheses. **ND - None Detected, method sensitivity: 0.0125 ppmA noninterference study for monensin was conducted by spiking control tissue samples with monensin plus bambermycins and roxarsone and then assaying these tissues for monensin content. The results demonstrated no interference by bambermycins and roxarsone on the tissue assay for monensin.
A noninterference study for roxarsone was conducted by spiking tissues with roxarsone plus bambermycins and monensin and then assaying these tissues for roxarsone content. The results of the data demonstrate no interference by bambermycins and monensin with the tissue assay for roxarsone.
Based upon the established withdrawal times for monensin and roxarsone, no drug residues were above the tolerance in any tissues from these broilers. These data support a 5-day withdrawal for the monensin/roxarsone/bambermycins combination.
VII. AGENCY CONCLUSIONS:
The data submitted in support of this supplemental NADA comply with the requirements of Section 512 of the Act and demonstrate that monensin (90-110 g/ton) plus bambermycins (1-2 g/ton) plus roxarsone(22.7 to 45.4 g/ton) are safe to the broiler chickens and effective for the claims indicated in Section 2 of this FOI Summary.
The sponsor has demonstrated through residue depletion studies that residues of monensin and roxarsone deplete below tolerance levels in edible tissues of chickens during a 5-day drug withdrawal period and that bambermycins residues are at a safe concentration at zero withdrawal. A regulatory method of analysis is not required for bambermycins in broiler chicken tissues. A practical regulatory analytical method for monensin and roxarsone in chicken tissues are in FDA's Food Additive Manual on public display in Room 12-A-30, 5600 Fishers Lane, Rockville, Maryland 20852.
The approval of this supplemental NADA poses no significant increase in the frequency of human exposure to residues of the three drugs. The sponsor has adequately demonstated that residues from either drug do not interfere with the assay of the other drug in chicken tissues. This is a Category II supplemental NADA that did not require reevaluation of the basic human food safety data in the parent NADAs. The edible tissue from broiler chickens fed this combination drug is safe for food purposes when the 5-day withdrawal period is observed.
Non-interference studies demonstrated that monensin with or without roxarsone plus bambermycins prevented an outbreak of coccidiosis when exposed to the six major species of the organism that cause coccidiosis. The data from four well-controlled floor-pen studies demonstrate the effectiveness of bambermycins at 2-grams per ton in the presence of monensin (110 g/ton) plus roxarsone (45.4 g/ton) for increased rate of weight gain in broiler chickens. These data satisfy the requirements for full range approval for bambermycins, 1-2 g/ton, in combination with monensin (90 to 110 g/ton) plus roxarsone (22.7 to 45.4 g/ton) for increased rate of weight gain and for the prevention of coccidiosis under the CVM Policy outlined in the revised (October 1983) combination drug guidelines (48 FR 51537).
VIII. LABELING (Attached)
Copies of applicable labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855