Approval Date: April 14, 1992
I. GENERAL INFORMATION:
163 Avenue Gambetta
75020 Paris, France
Hoechst Roussel Agri-Vet Company
Rt. 202-206 North
Somerville, New Jersey 08876
Effect of Supplement:
Change of tolerance.
II. INDICATIONS FOR USE
For the prevention of coccidiosis caused by Eimeria adenoeides, E. meleagrimitis, and E. gallopavonis in growing turkeys
III. DOSAGE FORM(S), ROUTE(S) OF ADMINISTRATION, AND RECOMMENDED DOSAGE
Stenorol® is supplied as a Type A Medicated Article in 50 lb. multi-walled bags. The Type A Medicated Article contains 6 grams of halofuginone hydrobromide per kg of premix (2.72 grams halofuginone hydrobromide per pound of premix). The drug is administered orally by mixing one half (1/2) to one (1) pound of the Type A Medicated Article into one (1) ton (2,000 lb) of Type C Medicated feed. The dosage is 1.36 to 2.72 g/ton halofuginone hydrobromide in Type C Medicated turkey feed.
This information is addressed in the original FOI for halofuginone hydrobromide for growing turkeys (FR 28051; July 5, 1989).
V. ANIMAL SAFETY
This information is addressed in the original FOI for halofuginone for growing turkeys (FR 28051; July 5, 1989).
Vl. HUMAN FOOD SAFTY
A. Toxicity Tests
The toxicity studies summarized in the FOI from NADA 130-951 (halofuginone hydrobromide for broiler chickens - 50 FR 33718; August 21, 1985) have met the Agency's requirement for Human Food Safety. The toxicity studies in NADA 130-951 demonstrated that halofuginone hydrobromide is an eye and skin irritant and the following statement has been added to the labels.
Halofuginone hydrobromide has been found to be an eye and skin irritant. Avoid contact with skin, eyes or clothing. Avoid inhalation of dust. In case of contact remove contaminated clothing and immediately flush eyes or skin with plenty of water for 15 minutes. Get medical attention if irritation persists.
B. Safe Concentration of Total Residues and Tolerance for the Marker Substance.
The most sensitive species shown in the toxicity studies contained in NADA 130-951 (halofuginone hydrobromide for broiler chickens) was the mouse for which a no-observed-effect level (NOEL) of 0.07 mg/kg/day was found. For chronic toxicity a 100 fold safety factor is applied for calculating a safe concentration. The safe concentrations for total residues of halofuginone hydrobromide in the uncooked edible tissues of turkeys are 0.1 ppm in muscle, 0.3 ppm in liver and 0.2 ppm in skin with adhering fat.
Prior to the review conducted for this supplement, it had been concluded that a level of 0.1 ppm unchanged halofuginone hydrobromide (the marker substance) corresponded to a level of 0.3 ppm in turkey liver (the target tissue). A review of the residue study newly submitted with this supplement was conducted, and in that review it was concluded that 0.13 ppm is a more accurate level of unchanged halofuginone hydrobromide in turkey liver when total residues are at the safe concentration of 0.3 ppm. Accordingly, the tolerance for unchanged halofuginone hydrobromide in liver tissue is changed to 0.13 ppm with the approval of this supplement to NADA 140-824. The safe concentrations for total residues of halofuginone hydrobromide in the edible tissues of turkeys remain unchanged as listed above.
The residue studies and tolerance calculations that support the change in tolerance are described in Parts C and D that follow.
C. Residue Depletion and Metabolism
Total residues of 14C-halofuginone hydrobromide in tissues of turkeys were determined in a study, using halofuginone hydrobromide radiolabeled in the quinazolinone ring. The results of the study show that the measurement of radioactivity in tissues followed the pattern seen in previous studies with 14C-halofuginone hydrobromide in chickens (NADA 130-951). The investigator for this study was:
Dr. D. R. Hawkins, Huntingdon Research Centre Huntingdon, Cambridgeshire England.
The study was conducted as follows:
Twenty turkeys were given daily oral doses of 14C-halofuginone hydrobromide on 14 consecutive days. Each daily dose was 0.3 mg 14C-halofuginone hydrobromide which corresponds to a dietary incorporation of 3 ppm. Four turkeys (2 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.
(Eds. note: The following table consists of 5 columns.)
HOURS POST MEDICATION
Liver and pooled kidney tissues from the above total residue study were also assayed for parent halofuginone hydrobromide by an HPLC assay. The results of those assays indicate that parent halofuginone hydrobromide represents a significant portion of the total residue in both liver and kidney, but of the two tissues, liver has the overall depletion characteristics most favorable for the target tissue. The residue levels in liver tissue are shown below.
(Eds. note: The following table consists of 5 columns.)
AVERAGE LEVELS OF TOTAL RADIOACTIVITY AND OF PARENT HALOFUGINONE HYDROBROMIDE IN LIVER TISSUES OF TURKEYS TREATED FOR 14 DAYS AT 3 PPM
|Sacrifice Time Hours||Total radioactivity (ppm)||Halofuginone Hydrobromide (ppm)||% Halofuginone Hydrobromide|
A comparative metabolism study, conducted by Dr. Leon LeVan, Hazleton Laboratories America Inc., 3301 Kinsman Blvd., Madison, WI 53707, was completed in which eight (4 males and 4 females) turkeys were given six (6) consecutive oral doses of 0.3 mg 14C-labeled halofuginone hydrobromide/kg/day. The oral dose of 0.3 mg/kg corresponds to a dietary incorporation of 3 ppm halofuginone hydrobromide. In a separate study, conducted by Dr. D. R. Hawkins, Huntingdon Research Centre, Huntingdon, Cambridgeshire, England, thirty-six (18 males and 18 females) mice were given a single 0.24 mg/kg body weight oral dose of 14C-labeled halofuginone hydrobromide.
The dose corresponds to the high dose level in chronic toxicity studies. The turkeys were sacrificed 12 hours after the last dose and the mice were sacrificed 24 and 48 hours after dosing.
Extracts of turkey liver contained one major component by thin layer chromatography which corresponded to unchanged halofuginone hydrobromide (over 90%). Female mouse liver extract was shown to contain predominantely (85%) a component which corresponded to unchanged halofuginone hydrobromide 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 female mouse 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 turkey liver extracts were also present in extracts of mouse liver. Thus, it was concluded that a test species (the mouse) and the turkey were each qualitatively exposed to the same residues of halofuginone hydrobromide.
D. Determination of the Tolerance for the Marker Residue
The tolerance for unchanged halofuginone hydrobromide (the marker residue) in liver tissue was determined from data in a final total residue study (RSL 826/941335). That investigation was conducted with (14C-quinazolinone) halofuginone hydrobromide, and parallel assays were performed for total radioactivity and for the marker residue as measured by the regulatory assay.
Twenty-four turkeys (twelve of each sex) were given daily doses of 14C-halofuginone hydrobromide by gavage 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. The birds were killed in groups of six, three males and three females, at 24, 48, 72 and 96 hours after the final dose. The livers were removed from the birds, pooled according to sex and sacrifice time, and homogenized. Potions of the homogenates were assayed for total radioactivity and for unchanged drug by the regulatory assay for halofuginone hydrobromide. The results of those assays are shown below
(Eds. note: The following table consists of 4 columns.)
AVERAGE LEVELS OF TOTAL RADIOACTIVITY AND OF PARENT HALOFUGINONE HYDROBROMIDE IN LIVER TISSUES OF TURKEYS TREATED FOR 6 DAYS AT 3 PPM
|Sacrifice time (hours)||Total Radioactivity (ppm)||Halofuginone Hydrobromide ppm||% of total residue|
The residue depletion curves representing the above data show that, when the average total residue in liver (the target tissue) is at the consumption adjusted safe concentration of 0.3 ppm, the level of parent halofuginone hydrobromide (the marker residue) is 0.13 ppm. The Rm or tolerance was thus determined to be 0.13 ppm halofuginone hydrobromide in turkey liver.
E. Withdrawal time
The withdrawal time for this drug use was determined from a residue study in which turkeys were treated with unlabeled halofuginone hydrobromide. The investigators for this study were:
Drs. P. Griminger and H. Fisher
Dept. of Nutrition
Rutgers, The State University
New Brunswick, NJ 08903
The birds in this study were treated continuously from 1 day of age to 12 weeks of age with halofuginone hydrobromide at 3 ppm (2.72 g/ton) in the feed. Six birds (3 males and 3 females) were sacrificed at 0, 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 average residue levels and the standard deviation are presented in the table below.
(Eds. note: The following table consists of 5 columns.)
AVERAGE RESIDUE LEVELS (PPM) OF HALOFUGINONE HYDROBROMIDE IN THE LIVERS OF TURKEYS TREATED CONTINUOUSLY WITH UNLABELED DRUG AT 3 PPM
|Day 0||Day 2||Day 3||Day 4||Day 5|
The statistical analysis of the liver residue depletion data at days 2, 3, 4 and 5 using the upper limit containing 99 percentlie of the population with 95% confidence showed that residues of halofuginone hydrobromide deplete to below 0.13 ppm after six days of withdrawal. However, because a request to reduce the withdrawal time was not part of this supplement to NADA 140-824, the withdrawal time for halofuginone hydrobromide in turkeys remains at seven days.
F. Regulatory Methods
The determinative method for measuring quantitatively residues of halofuginone hydrobromide in poultry (turkey and chicken) liver has been validated and is based on high pressure liquid chromatography. The validated confirmatory assay is a mass spectrometry/mass spectrometry procedure. The regulatory methods are filed in the Food Additives Manual on display in FDA's Freedom of Information Public Room (room 12A-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 to prevent coccidiosis in broiler chickens and growing 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. The metabolism data demonstrate that when total drug residues of halofuginone in turkey liver (the target tissue) have depleted to the safe concentration of 0.3 ppm, the level of unchanged halofuginone (the marker residue) is approximately 0.13 ppm rather than 0.1 ppm. The safe concentrations for total residues in the uncooked edible tissues of turkeys remain 0.1 ppm in muscle, 0.3 ppm in liver and 0.2 ppm in skin with adhering fat. The withdrawal time remains at seven (7) days.
Under the Center's supplemental approval policy [21 CFR 514.106(b)(2)], this is a Category II change. The change in tolerance for residues of the halofuginone marker residue in turkey liver was based on a review of newly submitted metabolism data and our a re-review of the residue and metabolism data contained in the original NADA. The newly submitted data demonstrate that 0.13 ppm is a more accurate level of unchanged halofuginone (the marker residue) in turkey liver (the target tissue) when total residues in that tissue are at the safe concentration of 0.3 ppm.
The change in tolerance was based solely on the review of the metabolism data, and a re-evaluation of the toxicity data supporting the safe concentration of total drug related residues of halofuginone was not required. Approval of this change in tolerance is not expected to pose an increased risk to human food safety because the safe concentration of residues of halofuginone and the withdrawal time for the drug were not changed.
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 Food Safety Data Submitted in a Supplemental Application." The policy states that the provision of exclusivity does not apply to human food safety studies submitted to obtain a different tolerance, because the tolerance for a drug substance applies to all products containing the same drug substance. In this case, the newly established tolerance will apply immediately to any generic products as well as the pioneer drug product. Therefore, this approval does not qualify for an exclusivity period under section 512 (c)(2)(F) of the Federal Food, Drug, and Cosmetic Act (the Act).
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