NADA 130-951 Stenorol® - supplemental approval (March 8, 1991)
Approval Date: March 8, 1991
I. GENERAL INFORMATION:
Roussel Uclaf, Div. Agro-Veterinaire
P.O. Box 2500
Route 202-206 North
Sommerville, NJ 08876-1258
Over the Counter (OTC)
Effect of Supplement:
Change of tolerance.
II. INDICATION 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.
III. DOSAGE FORM(S), ROUTE(S) OF ADMINISTRATION, AND RECOMMENDED DOSAGE
Stenorol is supplied as a medicated premix in 50 lb. multi-walled bags. The premix contains 6 grams of halofuginone hydrobromide per kg of Type A Medicated article (2.72 grams halofuginone per pound of Type A Medicated Article). The drug is administered orally by mixing one (1) pound of Type A Medicated Article into one (1) ton (2,000 lbs) of complete feed. The dosage is 3 ppm halofuginone hydrobromide mixed into Type C Medicated feed for broilers.
This information is addressed in the original FOI for halofuginone hydrobromide for broiler chickens (FR 33718; Vol. 50, No. 162, August 21, 1985).
V. ANIMAL SAFETY
This information is addressed in the original FOI for halofuginone hydrobromide for broiler chickens (FR 33718; Vol. 50, No. 162, August 21, 1985)
VI. HUMAN FOOD SAFETY
A. Toxicity Tests
This information is addressed in the original FOI for halofuginone hydrobromide for broiler chickens (FR 33718: Vol. 50, No. 162, August 21, 1985)
B. Safe Concentration of Residues
The most sensitive species shown in the toxicity studies was the mouse for which a no-effect level (NOEL) of 0.07 mg/kg/day was found. For chronic toxicity a 100 observed-fold safety factor is applied for calculating a safe concentration. The safe concentration of total residues of halofuginone in the uncooked edible tissues of broilers are 0.1 ppm in muscle, 0.3 ppm in liver and 0.2 ppm in skin with adhering fat. Based on the data on the following section, (C. Residue Depletion and Metabolism) halofuginone hydrobromide has an established tolerance in broilers of 0.16 ppm for parent halofuginone hydrobromide (marker residue) in liver (target tissue). A marker residue concentration of 0.16 ppm in liver corresponds to a concentration for total residues of halofuginone hydrobromide of 0.3 ppm in liver.
C. Residue Depletion and Metabolism
Total residues of 14-C-halofuginone in tissues of chickens were determined in two studies, one using halofuginone radiolabeled in the piperidine ring and one with halofuginone radiolabeled in the quinazolinone ring. The results of the two studies were similar showing that extensive metabolism into components containing only the piperidine or quinazolinone moieties does not occur. The data from the study using 14-C-piperidine ring labeling are shown in the following table as that study gave somewhat higher total residues values in the mid range of that depletion curve for liver tissue. The investigator for this study was:
Dr. D. R. Hawkins
Huntingdon Research Centre
Thirty-six broilers were given daily oral doses of 14-C-halofuginone on 14 consecutive days. Each daily dose was 0.3 mg 14-C-halofuginone which corresponds to a dietary incorporation of 3 ppm. Six broilers (3 of each sex) were sacrificed at each time point. The average total residue levels (in ppm) observed at each sacrifice interval and the corresponding standard deviation are shown below (Table 1).
(Eds. note: The following table consists of 7 columns.)
|0.25 Day Post-Medication||1 Day Post-Medication||2 Days Post-Medication||3 Days Post-Medication||4 Days Post-Medication||6 Days Post-Medication|
Liver and pooled kidney tissues from the above total residues study were also assayed for parent halofuginone by HPLC assay. The results of those assays showed that parent halofuginone represents a significant portion of the total residue in both liver and kidney, but of the two tissues, liver had the overall depletion characteristics most favorable for the target tissue.
Dr. Leon LeVan, Hazleton Laboratories America, Inc., Madison, WI 53707, conducted the final 14-C-halofuginone hydrobromide residue study in broiler liver to determine the tolerance for parent halofuginone hydrobromide in broiler liver. Twenty-four broilers (twelve of each sex) were given daily doses of 14-C-halofuginone hydrobromide for six consecutive days. Each daily dose was 0.3 mg/kg body weight which corresponds to a dietary incorporation of 3 ppm halofuginone hydrobromide. Six broilers (three of each sex) were sacrificed at 24, 48, 72 and 96 hours after the final dose. The average total residues (total radioactivity) and the parent compound (halofuginone hydrobromide) recovered are shown in Table 2. Based on these data, when the average total residue in the liver (target tissue) is at the consumption adjusted safe concentration of 0.3 ppm, the parent halofuginone hydrobromide (the marker residues) equals 0.16 ppm. The Rm or tolerance, was thus determined to be 0.16 ppm halofuginone hydrobromide in broiler liver.
(Eds. note: The following table consists of 4 columns.)
Table 2 AVERAGE LEVELS OF TOTAL RADIOACTIVITY AND OF PARENT HALOFUGINONE IN LIVER TISSUES OF CHICKENS TREATED FOR 6 DAYS AT 3 PPM
|Sacrifice Time (Hours)||Total Radioactivity (ppm)||Halofuginone ppm||Hydrobromide % of Total Residue|
A comparative metabolism study was completed in which six female chickens were given a single oral dose of 5 mg/kg body weight (BW) 14-C-halofuginone hydrobromide and twelve mice (6 males, 6 females) were given a single 0.24 mg/kg BW oral dose of 14-C-halofuginone hydrobromide. This study was conducted by Dr. D. R. Hawkins, Huntingdon Research Centre, Huntingdon, England.
Extracts of chicken liver from birds killed at zero withdrawal contained predominantly one component which corresponded to unchanged halofuginone (94%). A small percentage (6%) of a less polar metabolite was also present. Female mouse liver extract was shown to contain predominantly (85%) a component which corresponded to unchanged halofuginone plus 15% of a more polar component. Male mouse liver extract contained as the major (51%) component a metabolite which was less polar than halofuginone hydrobromide and which was not present in the extracts of either female mouse liver or female chicken liver. In addition, 30% of a component corresponding to parent halofuginone hydrobromide was present in male mouse liver extract. On a qualitative basis, the radioactive components detected by chromatography of female chicken liver extracts were also present in extract of male and female mouse liver. A similar qualitative relationship was also demonstrated with the metabolite pattern for chicken excreta and for mouse urine and feces. Thus, it was concluded that a test species (the mouse) and the chicken were each qualitatively exposed to the same residue of halofuginone.
D. Tolerance for Marker Residue
The above data show that, when the average total residue level in liver (the target tissue) is at the consumption adjusted safe concentration of 0.3 ppm, parent halofuginone hydrobromide (the marker residue) represents approximately 53% of that residue or 0.16 ppm. The Rm or tolerance, was thus determined to be 0.16 ppm halofuginone hydrobromide in the liver.
E. Withdrawal Time
The withdrawal time for this drug use was determined from a residue study in which broiler chickens were treated with unlabeled halofuginone hydrobromide. The broilers were treated continuously from 1 day of age to 7 weeks of age (market weight) with halofuginone hydrobromide at 3 ppm in the feed. Six birds, (3 males and 3 females) were sacrificed at 0, 1, 2, 3, 4, and 5 days of withdrawal, and the livers were assayed for halofuginone hydrobromide (the marker residue) by the HPLC regulatory assay. The investigators for this study were Drs. Paul Griminger and Hans Fisher, Nutrition Dept., Rutgers, The State University, New Brunswick, NJ 08903. The average residue levels and the standard deviation are presented in Table 3.
(Eds. note: The following table consists of 6 columns.)
Table 3 Average Residue Levels (ppm) Of Halofuginone In The Livers Of Chickens Treated Continuously With Unlabeled Drug At 3 ppm
|Day 0||Day 1||Day 2||Day 3||Day 4||Day 5|
|0.84 (.19)||0.33 (.09)||0.14 (.05)||0.06 (.03)||0.02 (.004)||0.002 (.005)|
The statistical analysis of the depletion data using the upper tolerance limit containing 99 percentile of the population with 95% confidence yields a withdrawal period of 4 days for this drug use. The analytical method used to generate the depletion data has lower limit of reliable measurement of 0.05 ppm, and values below that level were not used in the statistical analysis.
F. Regulatory Methods
The determinative method for quantitating residues of halofuginone in chicken liver is based on high-pressure liquid chromatography. The confirmatory assay is a negative ion chemical ionization spectrometry/mass spectrometry procedure.
The determinative and confirmatory methods were validated satisfactorily by FDA and USDA laboratories. The validated regulatory methods are filed in the Food Additives Manual on display in FDA's Freedom of Information Public Room (room 12-A-30, 5600 Fishers Lane, Rockville, MD 20857).
VII. AGENCY CONCLUSIONS
Halofuginone hydrobromide, codified in 21 CFR 558.265 and CFR 556.308, is approved for marketing as a Type A Medicated Article for use for the prevention of coccidiosis in broiler chickens and turkeys.
The data submitted in support of this supplemental NADA requesting an increase in the tolerance satisfy the requirements of section 512 of the Act and demonstrate that halofuginone hydrobromide (STENOROL®) at a concentration of 3 ppm in finished feed, will produce 0.3 ppm total concentration of residues in the liver (target tissue) of broiler chickens. This concentration corresponds to a concentration of parent halofuginone (marker residue) of 0.16 ppm (rather than 0.1 ppm), in liver. The safe concentrations for total residues in the uncooked edible tissues of broiler chickens remain 0.1 ppm in muscle, 0.3 ppm in liver and 0.2 ppm in skin with adhering fat and the withdrawal period for such chickens remains 4 days.
Under the Center's supplemental approval policy, this is a category II change [21 CFR 514.106 (b)(2)(xi)]. The approval of this change, a recalculation of the tolerance, is not expected to have any adverse effect on the safety or effectiveness of this new animal drug. The change in tolerance requires no change in either the safe concentration or the withdrawal period, i.e., an increase in residue concentration is not expected. Accordingly, this approval did not require a reevaluation of the safety and effectiveness data in the parent application.
In implementing the Generic Animal Drug and Patent Restoration Act, the Center's third policy letter published August 28, 1989 (54 FR 35534) discusses "Exclusivity for Human Safety Data Submitted in Supplemental Application." The Center's policy states that the provision of exclusivity does not apply in the case of human food safety studies submitted to obtain a different tolerance, because a tolerance for a drug necessarily applies to all products containing the same drug substance.
- Front of 50 pound bag Type A premix
- Back of 50 pound bag Type A premix
Copies of these 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.