Approval Date: March 28, 1996
Freedom of Information Summary
NADA 132-872
I. GENERAL INFORMATION:
NADA 132-872 Sponsor: Hoechst-Roussel Agri-Vet Co.
P. O. Box 2500
Route 202-206
Somerville, NJ 08876-1258Generic Name: fenbendazole Trade Name: Safe-Guard® Paste 10%; Panacur® Paste 10% Marketing Status: Over the Counter (OTC) Effect of Supplement: This supplement provides for the use of fenbendazole for the removal and control of gastrointestinal parasites and lungworm in dairy cattle of breeding age. II. INDICATIONS FOR USE AND LABEL DOSE:
BEEF AND DAIRY CATTLE- INDICATIONS DOSAGE
For the removal and control of: 5 mg/kg
Lungworm: (Dictyocaulus viviparus)
Stomach Worm (adults):
Brown Stomach worm (Ostertagia ostertagi).
Stomach Worm (adults & 4th stage larvae):
Barberpole Worm (Haemonchus contortus/placei),
Small Stomach Worm (Trichostrongylus axei).
Intestinal Worms (adults & 4th stage larvae):
Hookworm (Bunostomum phlebotomum),
Threadneck Intestinal Worm (Nematodirus helvetianus),
Small Intestinal Worms (Cooperia oncophora, Cooperia punctata),
Bankrupt Worm (Trichostrongylus colubriformis),
Nodular Worm (Oesophagostomum radiatum).
III. EFFECTIVENESS:
Efficacy was established in the original approval under NADA 132-872 and its supplements (46 FR 32018, June 19, 1981; 47 FR 15327, April 9, 1982; 49 FR 8433, March 7, 1984; and 50 FR 26358, June 26, 1985). No new studies were conducted to establish effectiveness associated with the use of fenbendazole in dairy cattle of breeding age.
IV. TARGET ANIMAL SAFETY:
Animal safety was established in the original approval under NADA 132-872 and its supplements (46 FR 32018, June 19, 1981; 47 FR 15327, April 9, 1982; 49 FR 8433, March 7, 1984; and 50 FR 26358, June 26, 1985). No new studies were conducted to establish animal safety associated with the use of fenbendazole in dairy cattle of breeding age.
V. HUMAN FOOD SAFETY:
A. Toxicity Tests:
Toxicity and teratogenicity studies were presented in the original NADA 128-620 and were conducted in Hoechst Research Laboratories in Frankfurt, Germany and in the United States. Fenbendazole was determined to be safe to human health when food derived from treated animals is ingested (48 FR 42809, September 20, 1983).
B. Safe Concentrations and Tolerances
Safe concentrations for fenbendazole total residues in cattle tissues were established with the original NADA 128-620 and are listed below along with the tissue consumption factors that were used.
Tissue Safe Concentration muscle 5 ppm liver 10 ppm (factor of 2) kidney l5 ppm (factor of 3) fat 20 ppm (factor of 4)The tolerance and marker residue for fenbendazole in cattle also were assigned with the original NADA 128-620. The tolerance in cattle liver (the target tissue) is 0.8 ppm parent fenbendazole (the marker residue) as measured by the regulatory assay.Newly established with this supplement to NADA 132-872 are a safe concentration and a tolerance for residues of fenbendazole in milk. The safe concentration for fenbendazole total residues in milk is set at 1.67 ppm (1/3 of the 5 ppm safe concentration in muscle tissue). The 1.67 ppm value was determined using FDA's approach to assigning safe concentrations based on food factors (44 FR 17070, March 20, 1979).
As explained in Part C below, the marker residue for fenbendazole in milk is the sulfoxide of parent fenbendazole. The tolerance is assigned at 0.6 ppm, although the marker residue never reaches that level in the milk from cattle treated at the approved dosing rate of 5 mg/kg body weight. The tolerance value was calculated from the marker residue to total residue percentage when total fenbendazole residues are at a maximum in milk. That maximum occurs in the range of 24 to 36 hours following dosing, and at that time, the sulfoxide represents approximately 35% of the total residue present. Accordingly, the tolerance for the fenbendazole sulfoxide is set at 0.6 ppm (35% of the 1.67 ppm safe concentration).
C. Total Residue and Metabolism Studies
Tissue residue depletion and metabolism studies in cattle were presented in the original NADA 128-620. Based on data from those studies, an eight (8) day withdrawal time in edible tissues (muscle, liver, fat, kidney) was established (48 FR 42809, September 20, 1983). The total residue studies summarized below were submitted with this supplement to describe fenbendazole residues in milk.
Milk Total Residue Study.
A study designed to measure residues in milk from one untreated and five 14C fenbendazole-treated lactating dairy cattle was conducted to determine the total residue profile as a function of time, to identify metabolites of fenbendazole in milk, and to select a marker substance to monitor residues in milk of lactating dairy cattle.
Study No. U.S. Dairy Cow Milk Residue Study LAV #1506 SVM (LSU Account # 166-60-6166) Starting Date January 31, 1992 End Date August 5, 1993 Study Director Dr. Steven A. Barker School of Veterinary Medicine Louisiana State University Baton Rouge, LA 70803 Identification of Substance and 14C-fenbendazole 1.89 mCi/g in aqueous Dosage Form suspension Species and Age Holstein, 33 months to 7 years Number of Animals/weight Six lactating dairy cows; average 603 kg Drug Level Tested 5.0 mg/kg body weight Route of Administration Oral, administered once
After an acclimatization period, a morning milk sample was taken from each cow prior to treatment. This sample served as a blank control for the study. Following this milking, five cows received fenbendazole suspension by stomach tube. This aqueous suspension of labeled (14C) fenbendazole and unlabeled fenbendazole contained approximately 2 mCi activity/g. The amount of fenbendazole administered to each cow by stomach tube was calculated to equal 5.0 mg/kg body weight. The stomach tube was flushed with suspension solution to assure complete delivery. A control cow received suspension solution which did not contain fenbendazole. Morning and afternoon milk samples were collected for six days following drug administration. After six days the residues were below the level of detection.Total residues for each whole milk sample from each cow were determined by scintillation counting. Each sample was assayed in triplicate by dissolving 0.5 mL aliquots of blended sample in 12 mL of scintillation cocktail. Before counting, each sample was placed in the dark for one hour to reduce contributions from chemiluminescence. Selected whole milk samples were also centrifuged, and 0.5 mL aliquots of fat and water portions were counted to determine label distribution.
For metabolic profiling, milk samples were extracted by matrix solid phase dispersion (MSPD) techniques, and the absolute recovery of total label was determined by scintillation counting of the extracts. The distribution of the extracted label between remaining parent drug and metabolites was determined by HPLC analyses using UV diode array and in-line radiolabel detection. The identity of radiolabeled peaks was matched with known standards for the metabolites of fenbendazole based on retention time and UV-diode array spectra. Samples were also assayed quantitatively by HPLC using an internal (mebendazole) standard and correcting for recovery.
The results from the radiolabel assay for total residues in whole milk and the HPLC analyses of metabolites in whole milk averaged for the five cows as a function of time are presented in Table 1.
Table 1. Average Concentrations of Total Residues and Metabolites of Fenbendazole in Whole Milk as a Function of Time Following Oral Administration of 5.0 mg Fenbendazole/kg Body Weight to Five Lactating Dairy Cows*. Day, Milking Total Residue FBZ-SO (± SD) FBZ-SO2 (± FBZ/Total (± SD) µg/mL µg/mL n = 5 SD) µg/mL n = Residue x 100 n = 5 (Sulfoxide) 5 (Sulfone) Ratio % 1, am (Time 0) 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 1, pm 0.060 ± 0.043 0.026 ± 0.025 0.000 ± 0.000 43.333 2, am 0.482 ± 0.076 0.232 ± 0.045 0.018 ± 0.011 48.133 2, pm 0.526 ± 0.111 0.186 ± 0.005 0.024 ± 0.013 35.361** 3, am 0.408 ± 0.102 0.158 ± 0.026 0.062 ± 0.016 38.725 3, pm 0.298 ± 0.086 0.088 ± 0.034 0.046 ± 0.033 29.530 4, am 0.186 ± 0.080 0.030 ± 0.030 0.046 ± 0.024 16.129 4, pm 0.108 ± 0.044 0.006 ± 0.013 0.014 ± 0.017 5.555 5, am 0.054 ± 0.030 0.000 ± 0.000 0.010 ± 0.017 0.000 5, pm 0.024 ± 0.015 0.000 ± 0.000 0.000 ± 0.000 0.000 6, am 0.012 ± 0.008 0.000 ± 0.000 0.000 ± 0.000 0.000 6, pm 0.000 ± 0.000 0.000 ± 0.000 0.000 ± 0.000 0.000 *All residue levels were below the target of 0.83 ppm for the 1X tracer study (one-half the 1.67 ppm established safe concentration). No residues were detected in milk from the placebo (control) cow. **Ratio percent used to calculate tolerance level.At all times following administration of fenbendazole to lactating dairy cattle, residues in milk of fenbendazole and its metabolites were below the established safe concentration, and the total residue was evenly distributed between the fat and aqueous fractions of the whole milk.
Metabolic profiling of the total residues indicated that the concentration of parent drug in milk was negligible. The sulfoxide and sulfone metabolites of fenbendazole were the compounds that contributed to milk residues. The sulfoxide metabolite of fenbendazole was established to be the marker residue as it was present at levels significantly higher than parent fenbendazole or its sulfone metabolite. No other metabolites of fenbendazole were found in milk.
Milk Tolerance Calculation.
In Table 1 above, the ratio percent value of fenbendazole sulfoxide, the marker residue, to total residues was 35.4% at 36 hours following fenbendazole administration. At this time total residues in milk were greatest. The tolerance was calculated by multiplying the ratio percent of fenbendazole sulfoxide to total residues by the safe concentration (1.67 ppm). The tolerance was established to be 0.6 ppm (600 ppb).
D. Calf Tissue Total Residue Study.
A study was conducted to measure residues in calves born to 14C fenbendazole-treated dairy cattle. Total residue profiles in calf liver, kidney, fat and muscle were measured to provide data demonstrating the extent to which fenbendazole and its metabolites are transferred to and retained by the tissues of calves born to fenbendazole-treated cows.
Study No. U.S. Dairy Calf Tissue Residue Study LAV #1507 SVM (LSU Account # 166-60-6167) Starting Date April 21, 1992 End Date August 5, 1993 Study Director Dr. Steven A. Barker School of Veterinary Medicine Louisiana State University Baton Rouge, LA 70803 Identification of Substance and 14C-fenbendazole, 1.89, 1.95 and 2.09 mCi/g Dosage Form in aqueous suspension Species and Age Holstein, 3 years old or older Number of Animals/weight Six pregnant dairy cows; average 616 kg Drug Level Tested 5.0 mg/kg body weight Route of Administration Oral, administered once to the cowEight days prior to anticipated calving, six pregnant dairy cows were moved to an approved facility for acclimation and for study conduct. Three days after the start acclimation, each cow was administered fenbendazole by stomach tube at a dose calculated to equal 5.0 mg/kg body weight. The drug was administered as an aqueous suspension of labeled (14C) and unlabeled fenbendazole and contained approximately 2 mCi activity/g. One of the six cows was administered carrier only and was the control for the study. The calf from the control cow and calves from three cows receiving fenbendazole were delivered by cesarean surgery approximately 70 hours after dosing; the other two calves from treated cows were delivered by natural birth at 4 and 25 hours post-dosing. One calf died 5 hours after delivery, three treated calves and the control calf were sacrificed 24 hours after delivery, and one treated calf was sacrificed 48 hours after delivery. Surviving calves received colostrum from treated dams and milk replacer as needed for 24 to 48 hours after birth and prior to sacrifice.
Total residues for the described tissues were determined by oxidation of 0.5 g tissue samples in triplicate and scintillation counting (Table 1). Each sample was placed in the dark for one hour to reduce contributions from chemiluminescence.
Table 1. Concentrations of Total Residues of Fenbendazole and Metabolites in Calf Tissues Following Administration of 5.0 mg Fenbendazole/kg Body Weight to Five Pregnant Dairy Cows. Tissue Total Residue (µg/g) liver 1.398 ± 0.998* kidney 0.528 ± 0.383 fat 0.386 ± 0.400 muscle 0.306 ± 0.236 *mean ± SD; n = 5For metabolic profiling, liver tissue from one calf was extracted by matrix solid phase dispersion (MSPD) techniques, and the absolute recovery of total label was determined by scintillation counting of the extracts. The distribution of the extracted label between parent drug and metabolites was determined by HPLC analyses using UV diode array and in-line radiolabel detection. The identity of radiolabeled peaks was matched with known standards for the metabolites of fenbendazole based on retention time and UV-diode array spectra.
Results indicated that the label was distributed between the sulfone (34%) and sulfoxide (58%) metabolites of fenbendazole and parent fenbendazole (8%). No other radiolabeled metabolites were observed in the liver. Profiles of kidney, fat and muscle tissue from all calves using HPLC indicated the presence of the sulfoxide and sulfone metabolites. The parent drug, fenbendazole, was present in trace quantities. No other metabolites were indicated.
It was concluded from the residue data above, that in calves born to and consuming colostrum from fenbendazole-treated dams, residues of fenbendazole in liver, kidney, fat and muscle were below the established safe concentrations. Residue levels in liver, kidney, fat and muscle as a percent of the safe concentrations were 13.98%, 3.52%, 1.93% and 6.12%, respectively. Therefore, meat from calves born to fenbendazole-treated dams is safe even when fenbendazole is administered prior to parturition.
E. Milk Residue Tolerance Study.
A study with non-radiolabeled fenbendazole was conducted to determine the total quantity of fenbendazole and its metabolites in whole milk as a function of time and to expand the examination to include use of the actual market formulation. A further objective was to determine whether incurred fenbendazole residues or its metabolites demonstrate activity in three commonly used milk antibiotic screening tests, Charm II assay, Delvotest P, and Bacillus stearothermophilis disc assay. For this study fenbendazole paste 10% at a rate of 5 mg/kg body weight was administered to ten lactating dairy cows; an additional cow served as a control.
Study No. U.S. Dairy Cow Milk Residue Study LAV #1591 SVM (LSU Account # 166-60-6172) Starting Date November 3, 1992 End Date July 16, 1993 Study Director Dr. Steven A. Barker School of Veterinary Medicine Louisiana State University Baton Rouge, LA 70803 Identification of Substance and Fenbendazole, Safe-Guard® Paste 10% (100 Dosage Form mg/g) Species and Age Holstein, > 20 kg milk per day Number of Cows/weight Eleven lactating dairy cows; average 530 kgs Drug Level Tested 5.0 mg/kg body weight Route of Administration Oral, administered onceAnimals used in this study were selected from the Holstein herd maintained at the LSU Agricultural Experimental Station. All lactating dairy cows were at least thirty days postpartum and were producing a target minimum of 20 kg of milk per day. Animals were managed in the same manner as the remaining cow herd. The ration consisted of concentrate and corn silage, and the cows grazed Bermuda and rye grass. Cows were monitored for reproductive function, were bred by artificial insemination, and were treated for reproductive dysfunction according to standard herd practices.
Cows were weighed within twenty-four (24) hours of drug administration. The ten treated cows received Safe-Guard® Paste 10% in an amount to equal delivery of 5.0 mg fenbendazole/kg body weight. The control cow was untreated.
Cows were machine milked in the morning prior to treatment. Milk samples were collected at that milking and were used as blank controls for the study. Milk samples (100 mL) were then collected at the 4:00 AM and 4:00 PM milkings for seven days following fenbendazole treatment.
For metabolic profiling, milk samples were extracted by matrix solid phase dispersion (MSPD) technique. The amount of parent drug and metabolites was determined quantitatively by HPLC analyses using UV diode array detection. The identity of peaks was matched with known standards for the metabolites of fenbendazole based on retention time and UV-diode array spectra.
The administration of fenbendazole at a target dose of 5.0 mg/kg body weight as paste 10% to lactating dairy cows produced residues in whole milk identifiable as fenbendazole sulfoxide, fenbendazole sulfone and trace quantities of fenbendazole. Peak residue time in milk was twenty-four (24) hours after administration, and the peak fenbendazole sulfoxide marker level was 0.24 ± 0.03 µg/mL (Table 1). No residues of fenbendazole were detected in the control cow.
Table 1. Concentrations of Fenbendazole and Marker Metabolites of Fenbendazole in Whole Milk as a Function of Time Following Oral Administration of Paste 10% (100 mg/gm) at a Rate of 5.0 mg Fenbendazole/kg Body Weight to Ten Lactating Dairy Cows. Time after FBZ Fenbendazole (± FBZ-SO (± SD), FBZ-SO2 (± SD), Administration SD), µg/mL, n= 10 µg/mL, n= 10 µg/mL, n= 10 (Sulfoxide)** (Sulfone) 0 nd* nd nd 12 nd 0.15 ± 0.06 0.01 ± 0.00 24 nd 0.24 ± 0.03 0.08 ± 0.01 36 nd 0.19 ± 0.03 0.11 ± 0.01 48 nd 0.10 ± 0.02 0.11 ± 0.01 60 nd 0.03 ± 0.01 0.08 ± 0.01 72 nd 0.00 ± 0.00 0.03 ± 0.00 *No residues detected. **Marker residueAntibiotic residue test screening was conducted on milk samples from three (3) treated cows chosen randomly. The samples were collected at 12 hour intervals for 72 hours post-dose . Tests performed included the Charm II assay, Delvotest P, and Bacillus stearothermophilis disc assay. Zero time samples were included in all antibiotic screening tests; Delvotest P and B. stearothermophilis disc assay also included milk collected from the control animal at 12 hour intervals for 72 hours post-dose. Examinations indicated that the incurred residues from cows receiving fenbendazole suspension 10% at a rate of 5.0 mg/kg body weight had no discernible or consistent effect on the assays in term of producing false positive or suspect sample results. No sample from any cow examined gave a "positive" response to the Delvotest P and Bacillus stearothermophilis disc assay. Assay results of ten antibiotic classes indicated that fenbendazole and its metabolites do not interfere or cross-react with any consistency in the Charm II assay.
It was concluded that the fenbendazole sulfoxide marker residue level was below the tolerance level, and therefore, total residues were below the established safe concentration for milk. A zero-day withdrawal period was approved for use of fenbendazole paste 10% in dairy cattle of breeding age. It was further concluded that use of fenbendazole does not interfere with the practice of antibiotic drug screening.
F. Milk Discard and Slaughter Time
A zero (0) milk discard time is established for fenbendazole in dairy cattle of breeding age. The milk residue depletion studies described in Parts C and E above demonstrate that the maximum levels of fenbendazole residues in milk are well below the 1.67 ppm safe concentration and 0.6 ppm tolerance when lactating dairy cows are treated at the approved dosing rate of 5 mg/kg body weight. Accordingly, no discard of milk is required following treatment with fenbendazole.
An eight (8) day withdrawal time in edible tissues (muscle, liver, fat and kidney) was established in the original NADA 128-620 (48 FR 42809, September 20, 1983) and applies to dairy cows treated with fenbendazole.
G. Regulatory Methods:
A regulatory milk assay method is not required because of the establishment of a zero (O) milk withdrawal period in lactating dairy cattle. However, an HPLC assay method is on file at FDA/CVM in Rockville, MD.
A regulatory tissue method was developed as part of the original fenbendazole approval. The method, entitled, "Determination Procedure for the Measurement of Fenbendazole in Bovine Liver Tissue", is on file at the FDA's Freedom of Information Office, 5600 Fishers Lane, Rockville, MD 20857.
VI. AGENCY CONCLUSIONS:
The data submitted in support of this supplement satisfy the requirement of Section 512 of the Federal Food, Drug, and Cosmetic Act (FFDCA). The toxicology data on fenbendazole that were submitted with the original NADA 128-620 have allowed the establishment of a safe concentration of 1.67 ppm for total residues of fenbendazole in milk. From the residue and metabolite data on fenbendazole in dairy cattle that was submitted with this supplement, a tolerance of 0.6 ppm is established as the tolerance for residues in milk of the fenbendazole sulfoxide metabolite (the marker residue). Because the maximum levels of residues found in milk of fenbendazole-treated cattle are well below the safe concentration and tolerance noted above, no discard of milk (zero milk withdrawal) is required. The slaughter withdrawal time of 8 days required for treated dairy cattle is the same as established for beef cattle under the original NADA 132-872.
Under the Center's supplemental approval policy [21 CFR 514.106(b)(2)(v and x)], the addition of dairy cattle to the claim is a Category II change. The approval of this change is not expected to have any adverse effect on the safety or effectiveness of this new animal drug. Accordingly, this approval did not require a reevaluation of the safety and effectiveness data in the parent application.
Under section 512(c)(2)(F)(iii) of the FFDCA, this approval for food producing animals does not qualify for exclusivity because the supplemental application does not contain new clinical or field investigations (other than bioequivalence or residue studies) and new human food safety studies (other than bioequivalence or residue studies) essential to the approval and conducted or sponsored by the applicant.
VII. LABELING (Attached)
Supplement labels: #1. Safe-Guard® (fenbendazole) Paste 10% syringe label for cattle including dairy cattle of breeding age. 3.2 oz.
#2 Panacur® (fenbendazole) Paste 10% syringe label for cattle including dairy cattle of breeding age. 3.2 oz.
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.