• 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 140-818 Producil - original approval

Approval Date: July 24, 1992

I. GENERAL INFORMATION:

NADA 140-818
Sponsor: Merck Research Laboratories
Division of Merck & Company, Inc.
P. O. Box 2000
Rahway, New Jersey 07065
Generic Name: efrotomycin
Trade Name: Producil
Marketing Status:  

 

II. Indications for Use:

Weight Gain:

  • For increased rate of weight gain when incorporated into complete swine feeds at 3.6 to 14.5 g/ton. Feed Efficiency:
  • For improved feed efficiency when incorporated into complete swine feeds at 3.6 g/ton.

 

III. Dosage:
  1. Form: A free-flowing, non-dusty, granular premix containing 32 grams of efrotomycin activity per kilogram intended for incorporation in swine rations.
  2. Route of administration: Orally as an additive to swine feeds.
  3. Recommended dosage: The effective range for efrotomycin use in swine is 4 to 16 ppm (3.6 to 14.5 g/ton) inclusive for increases in average daily gain and 4 ppm (3.6 g/ton) for improvements in feed efficiency. Blend Producil into complete swine feeds at 4 oz - 16 oz per ton to supply 3.6 g - 14.5 g efrotomycin per ton of feed.

 

IV. Effectiveness:

Efficacy Studies

Efrotomycin, a natural fermentation product of a soil microorganism Nocardia lactamdurans, has activity against some gram-positive bacteria. Its antibacterial activity is a result of interference with bacterial protein synthesis. The mechanism for improving growth and feed conversion in pigs has not been defined.

Several experimental studies were conducted in the Merck Research Laboratories indicated that efrotomycin increased weight gains and improved feed efficiency in swine. This observation was verified by results from several range-finding studies in swine. The levels at which efrotomycin is effective in improving swine productivity were determined.

Six dose-titration/confirmation studies were conducted, according to one protocol, at five different locations by five different investigators. A minimum of four replicates of five treatment groups with 4-6 pigs per pen was used in each study. Following an adequate acclimation period, the individually identified pigs at about 5 weeks of age were weighed, ranked by weight within sex, and grouped into groups of five consecutively ranked pigs of the same sex. Pigs within each group of five were randomly allocated to pens within replicates, which consisted of sets of five contiguous pens. Treatments were randomly allocated to pens within each replicate.

Producil was incorporated into the ration to provide efrotomycin levels of 0, 2 (1.8 g/ton), 4 (3.6 g/ton), 8 (7.3 g/ton) and 16 ppm (14.5 g/ton), which corresponded with treatment groups 1 through 5, respectively. The pigs were weighed individually at the time of allocation, at least once each 28-day interval during the course of each study, and at termination of the study. Ration changes were generally coordinated with the regular weighings of the pigs. Any pigs that died during the course of a study were necropsied and subjected to pertinent laboratory tests to determine probable cause of death. The studies were terminated when the heaviest group of pigs reached market weight, an average of 120 days duration. All pigs in a study were given their final weighing on the same day.

The variables of interest were weight gain and feed efficiency. Weight gain and feed efficiency was measured and analyzed for the entire trial period, i.e., from trial initiation to termination. The pen was the experimental unit for all analyses. The studies were combined for analysis using analysis of variance and linear-plateau modeling methods. Also, in each analysis, the efrotomycin groups were compared individually to the nonmedicated control group, using one-degree-of-freedom contrasts, each with a one- sided significance level of 0.05.

ASR #10852
One hundred Hampshire/Yorkshire crossbred pigs, approximately 5 weeks of age and averaging 8.7 kg bodyweight, were used. Four replicates of five pens each were formed. Each pen contained five pigs. Three replicates included three male castrates and two females in each pen, while the fourth replicate included two male castrates and three females per pen. The pigs were fed starter ration that contained the respective efrotomycin treatment levels for the initial 28 days. After 28 days, they were moved into grower/finisher facilities. The pigs were fed a grower ration for 70 days and then a finisher ration for the next 26 days.

Three pigs were removed from the study and necropsied because of morbidity. One had an injured leg and interstitial pneumonia, another had acute enteritis and interstitial pneumonia and the third had a rectal prolapse. These pigs were from the treatment group levels of 4 (3.6 g/ton), 8 (7.3 g/ton) and 16 ppm (14.5 g/ton) treatment groups, respectively. No drug-related adverse reactions were observed during the course of the study. The following table is a summary of the data to Day 124.

Ed. note: The following table has 6 columns.

Efrotomycin Treatments ______________________________________________________ Nonmed. 2 ppm 4 ppm 8 ppm 16 ppm Variable Control (1.8 g/ton) (3.6 g/ton) (7.3 g/ton) (14.5 g/ton)

Number of pigs 20 20 20 20 20 Number of pens 4 4 4 4 4 Average weight(1) (kg), Day 0 8.7 8.7 8.7 8.8 8.7 Weight gain(1) (kg) to Day 124 81.0 86.0 86.5* 87.0* 87.0* (% increase (6.2%) (6.8%) (7.4%) (7.4%) over control) Feed efficiency(1,2) to Day 124 0.334 0.338 0.347 0.344 0.347 (% increase (0.9%) (3.8%) (2.9%) (3.7%) over control) Feed conversion(3) to Day 124 2.99 2.96 2.88 2.91 2.89

* Significantly (p < 0.05) greater than nonmedicated control mean (1) Arithmetic mean (2) Weight gain/weight of feed consumed (3) Harmonic mean (reciprocal of feed efficiency mean). This variable was not analyzed.

Dr. G. L. Cromwell - Study Director
Department of Animal Science
University of Kentucky
Lexington, KY 40546

ASR #10853
One hundred Hampshire/Yorkshire crossbred pigs used in this study were from the same herd as those used in ASR 10852. They were approximately 5 weeks old and averaged 7.8 kg bodyweight at the beginning of the study. Each pen contained five pigs. Two replicates included three castrated males and two females per pen and two replicates included two castrated males and three females per pen. The pigs were fed a starter ration until Day 28, a grower ration from Day 28 until Day 90, and a finisher ration from Day 90 until Day 125. The study was terminated at Day 125. The pigs were moved from the starter facility to grower/finisher facilities on Day 55.

Three pigs were removed from the study and necropsied because of morbidity. One pig had a fibrinopurulent pleuritis, one an abscessed forelimb and the third a gastric ulcer. These pigs had been fed efrotomycin at 0, 16 (14.5 g/ton) and 8 ppm (7.3 g/ton), respectively. No drug related adverse reactions were observed during the course of the study. The following table is a summary of the data to Day 125.

Ed. note: The following table has 6 columns.

Efrotomycin Treatments ______________________________________________________ Nonmed. 2 ppm 4 ppm 8 ppm 16 ppm Variable Control (1.8 g/ton) (3.6 g/ton) (7.3 g/ton) (14.5 g/ton)

Number of pigs 20 20 20 20 20 Number of pens 4 4 4 4 4 Average weight(1) (kg), Day 0 7.8 7.8 7.9 7.8 7.9 Weight gain(1) (kg) to Day 124 82.9 84.9 88.2* 84.2* 86.8* (% increase (2.4%) (6.4%) (1.6%) (4.7%) over control) Feed efficiency(1,2) to Day 124 0.328 0.337 0.343* 0.343* 0.342 (% increase (2.5%) (4.5%) (4.3%) (4.0%) over control) Feed conversion(3) to Day 124 3.04 2.97 2.91 2.92 2.93

* Significantly (p < 0.05) greater than nonmedicated control mean (1) Arithmetic mean (2) Weight gain/weight of feed consumed (3) Harmonic mean (reciprocal of feed efficiency mean). This variable was not analyzed.

Dr. G. L. Cromwell - Study Director
Department of Animal Science
University of Kentucky
Lexington, KY 40546

ASR #11240
One hundred twenty crossbred pigs, equally divided by sex, approximately 4 weeks of age and averaging 9.0 kg bodyweight, were used in this study. Four replicates of five treatment groups were formed. Three females and three castrated males were placed in each pen. The pigs were housed in the swine nursery for the initial 28 days, after which time, they were moved into the grower/finisher building. The pigs received a starter ration until Day 28, grower ration from Day 28 until Day 67, and finisher ration from Day 67 until termination of the study on Day 112. There were no deaths during the study nor were any drug-related adverse reactions observed. The following table is a summary of the data to Day 112.

Ed. note: The following table has 6 columns.

Efrotomycin Treatments ______________________________________________________ Nonmed. 2 ppm 4 ppm 8 ppm 16 ppm Variable Control (1.8 g/ton) (3.6 g/ton) (7.3 g/ton) (14.5 g/ton)

Number of pigs 24 24 24 24 24 Number of pens 4 4 4 4 4 Average weight(1) (kg), Day -2 9.0 9.0 9.0 9.0 9.0 Weight gain(1) (kg) to Day 112 76.4 81.3* 81.7* 82.2* 82.8* (% increase (6.4%) (6.9%) (7.5%) (8.4%) over control) Feed efficiency(1,2) to Day 112 0.372 0.387* 0.388* 0.386* 0.391* (% increase (3.9%) (4.2%) (3.8%) (5.1%) over control) Feed conversion(3) to Day 112 2.69 2.59 2.58 2.59 2.56

* Significantly (p < 0.05) greater than nonmedicated control mean (1) Arithmetic mean (2) Weight gain/weight of feed consumed (3) Harmonic mean (reciprocal of feed efficiency mean). This variable was not analyzed.

Dr. T. L. Veum - Study Director
Department of Animal Science
University of Missouri
Columbia, MO 65201

ASR #11242
One hundred twenty crossbred pigs, equally divided by sex, approximately 4 1/2 weeks of age and averaging 8.6 kg bodyweight, were used in the study. Six replicates of five treatment groups each were formed. Two females and two castrated males were placed in each pen. The pigs were housed in the nursery for the initial 28 days, moved to the grower unit for the next 56 days, and then moved to the finisher unit for the last 36 days of the 120-day grow-out period. The rations were changed from starter to grower to finisher when the pigs were moved.

One pig in the 4 ppm (3.6 g/ton) efrotomycin treatment group was removed from the study and necropsied. A severe bronchopneumonia was diagnosed. No drug-related adverse reactions were observed during the study. The following table is a summary of the data to Day 120.

Ed. note: The following table has 6 columns.

Efrotomycin Treatments ______________________________________________________ Nonmed. 2 ppm 4 ppm 8 ppm 16 ppm Variable Control (1.8 g/ton) (3.6 g/ton) (7.3 g/ton) (14.5 g/ton)

Number of pigs 24 24 24 24 24 Number of pens 6 6 6 6 6 Average weight(1) (kg), Day -1 8.5 8.6 8.6 8.6 8.6 Weight gain(1) (kg) to Day 120 80.7 83.8 85.5* 81.5 87.0* (% increase (3.9%) (6.0%) (1.0%) (7.8%) over control) Feed efficiency(1,2) to Day 120 0.350 0.357 0.368* 0.352 0.358 (% increase (2.0%) (5.0%) (0.4%) (2.3%) over control) Feed conversion(3) to Day 120 2.86 2.80 2.72 2.84 2.79

* Significantly (p < 0.05) greater than nonmedicated control mean (1) Arithmetic mean (2) Weight gain/weight of feed consumed (3) Harmonic mean (reciprocal of feed efficiency mean). This variable was not analyzed.

Dr. David H. Baker - Study Director
University of Illinois
Champaign-Urbana, IL 61801

ASR #11245
One hundred twenty crossbred pigs, equally divided by sex, approximately 4-1/2 weeks of age and averaging 8.2 kg. bodyweight, were used in the study. Four replicates of five pens each were formed. Three females and three castrated males were placed in each pen. The pigs were housed in the swine nursery for the initial 31 days, then moved to the grower/finisher building for the remaining 97 days of the study. The pigs were fed a starter ration for the initial 31 days, a grower ration for the next 53 days, and a finisher ration for the remaining 44 days of the 128-day grow-out period.

One pig in the 16 ppm (14.5 g/ton) died with a perforated rectum. Two pigs, one fed 4 ppm (3.6 g/ton) and the other 16 ppm (14.5 g/ton), had rectal prolapses. Neither pig was removed from the study; however, the latter required corrective surgery. No drug-related adverse reactions were observed during the course of the study. The following table is a summary of the data to Day 128.

Ed. note: The following table has 6 columns.

Efrotomycin Treatments ______________________________________________________ Nonmed. 2 ppm 4 ppm 8 ppm 16 ppm Variable Control (1.8 g/ton) (3.6 g/ton) (7.3 g/ton) (14.5 g/ton)

Number of pigs 24 24 24 24 24 Number of pens 4 4 4 4 4 Average weight(1) (kg), Day 0 8.2 8.2 8.2 8.3 8.2 Weight gain(1) (kg) to Day 128 81.5 87.2 84.2 84.4 89.0* (% increase (7.0%) (3.3%) (3.5%) (9.2%) over control) Feed efficiency(1,2) to Day 128 0.360 0.352 0.371 0.371 0.368 (% increase (-2.1%) (3.0%) (3.2%) (2.3%) over control) Feed conversion(3) to Day 128 2.78 2.84 2.70 2.69 2.72

* Significantly (p < 0.05) greater than nonmedicated control mean (1) Arithmetic mean (2) Weight gain/weight of feed consumed (3) Harmonic mean (reciprocal of feed efficiency mean). This variable was not analyzed.

Dr. T. R. Cline - Study Director
Baker Purdue Animal Science Center
Purdue University
West Lafayette, IN 47907

ASR #11247
One hundred forty Yorkshire-cross pigs, equally divided by sex, approximately 6-1/2 weeks of age and averaging 8.0 kg bodyweight, were used. The pigs were purchased from a commercial source and were given one week acclimation period at the study site. Following the acclimation period, the pigs were allocated by weight and sex to seven replicates of five pens. Each pen contained four pigs, two females and two castrated males, in each pen. The pigs remained in the grower/finisher building throughout the 112- day grow-out period. The pigs were fed a starter ration up to Day 28, a grower ration from Day 28 until Day 80, and a finisher ration from Day 80 until Day 112, when the study was terminated.

One pig 4 ppm (3.6 g/ton) died and one pig 16 ppm (14.5 g/ton) was removed from the study. Necropsy revealed an enterocolitis in the former and an ulcerated umbilical hernia in the latter. No treatment-related adverse reactions were observed during the course of the study. The following table is a summary of the data to Day 112.

Ed. note: The following table has 6 columns.

Efrotomycin Treatments ______________________________________________________ Nonmed. 2 ppm 4 ppm 8 ppm 16 ppm Variable Control (1.8 g/ton) (3.6 g/ton) (7.3 g/ton) (14.5 g/ton)

Number of pigs 28 28 28 28 28 Number of pens 7 7 7 7 7 Average weight(1) (kg), Day 0 8.1 7.9 8.0 8.1 7.9 Weight gain(1) (kg) to Day 112 73.6 80.6* 83.4* 85.5* 85.6* (% increase (9.5%) (13.3%) (16.2%) (16.3%) over control) Feed efficiency(1,2) to Day 112 0.343 0.354* 0.355* 0.360* 0.354* (% increase (3.0%) (3.4%) (4.8%) (3.1%) over control) Feed conversion(3) to Day 112 2.91 2.83 2.82 2.78 2.83

* Significantly (p < 0.05) greater than nonmedicated control mean (1) Arithmetic mean (2) Weight gain/weight of feed consumed (3) Harmonic mean (reciprocal of feed efficiency mean). This variable was not analyzed.

Dr. Roberto Alva-Valdes - Study Director
Merck Research Farm
Merck Research Laboratories
Fulton, MO 65251

These studies were conducted to determine the effectiveness of efrotomycin as a growth and efficiency enhancer for swine. These studies included a total of 29 replicates, using a total of 140 pigs for each treatment group. The pigs averaged 8.4 kg bodyweight at the beginning of the studies. The pigs were fed efrotomycin at 0, 2 (1.8 g/ton), 4 (3.6 g/ton), 8 (7.3 g/ton), and 16 ppm (14.5 g/ton) in commercial rations continuously over a 112- to 128- day growth-out period. The results, as summarized in the table that follows, indicate:

  1. A significant (p < 0.10) linear dose response in average daily gain throughout the range of inclusion levels of efrotomycin, which was observed through the complete test period. Percentage increases above the nonmedicated controls for average daily gain were 5.9% at 2 ppm (1.8 g/ton) and 8.9% at 16 ppm (14.5 g/ton). These data show that the effective range of inclusion levels of efrotomycin for increasing daily gain is 2 to 16 ppm (1.8 to 14.5 g/ton).
  2. Linear plateau analysis of feed efficiency data showed a significant (p < 0.05) linear dose response up to 4 ppm (3.6 g/ton) level of efrotomycin. The percentage increases above control ranged from 1.7% at 2 ppm (1.8 g/ton) to 4.0% at 4 ppm (3.6 g/ton). The results show that the effective range of inclusion levels of efrotomycin for improvement in feed efficiency is 2 (1.8 g/ton) to 4 ppm (3.6 g/ton).

Ed. note: The following table has 6 columns.

DATA SUMMARY OF ALL TRIALS FOR THE ENTIRE GROW-OUT PERIOD

Efrotomycin Treatments ______________________________________________________ Nonmed. 2 ppm 4 ppm 8 ppm 16 ppm Variable Control (1.8 g/ton) (3.6 g/ton) (7.3 g/ton) (14.5 g/ton)

Average daily gain(1) (kg) to trial termination Trial 10852 0.653 0.694 0.698 0.702 0.702 10853 0.663 0.679 0.705 0.673 0.694 11240 0.670 0.713 0.716 0.721 0.727 11242 0.667 0.693 0.707 0.673 0.719 11245 0.637 0.681 0.658 0.659 0.695 11247 0.651 0.714 0.738 0.757 0.757 Overall(2) 0.657 0.696* 0.704* 0.697* 0.716* (% increase over control) (5.9%) (7.1%) (6.2%) (8.9%) Feed efficiency(1,3) to trial termination Trial 10852 0.334 0.338 0.347 0.344 0.347 10853 0.328 0.337 0.343 0.343 0.342 11240 0.372 0.387 0.388 0.386 0.391 11242 0.350 0.357 0.368 0.352 0.358 11245 0.360 0.352 0.371 0.371 0.368 11247 0.343 0.354 0.355 0.360 0.354 Overall(2) 0.348 0.354* 0.362* 0.359* 0.360* (% increase over control) (1.7%) (4.0%) (3.2%) (3.4%) Feed conversion(4) 2.87 2.82 2.76 2.78 2.78 to trial termination

* Significantly (p < 0.5) greater than nonmedicated control mean (1) Arithmetic mean (2) Mean of trial means (3) Weight gain/weight of feed consumed (4) Harmonic mean (reciprocal of feed efficiency mean). This variable was not analyzed.

 

V. Target Animal Safety:

The safety of efrotomycin when used at the recommended use levels has been demonstrated in several range finding and dose titration studies. Additional studies were run to show that efrotomycin can be fed to pigs at greater than recommended use levels to demonstrate adequate safety margin.

Acute Toxicity (ASR # 11232)
This study was conducted to determine the clinical, clinical pathologic, gross pathologic and histopathologic effects of efrotomycin when fed to pigs at 16 ppm (14.5 g/ton), the highest recommended dose level and at 400 ppm (362.5 g/ton), 25 times the highest recommended dose level.

Nine castrated male and nine female, individually identified Yorkshire-cross swine weighing about 25 kg, were assigned randomly to one of three treatment groups. The pigs were housed individually. The pigs were fed a single basal ration, continuously for 21 days, that contained the premix carrier, efrotomycin at 16 ppm (14.5 g/ton), or efrotomycin at 400 ppm (362.5 g/ton). Initial and terminal body weights were recorded, as was feed consumption. Blood samples were collected prior to, during, and at the termination of the study. Semi-solid feces and perianal erythema were seen on a transient basis in some pigs in the 400 ppm (362.5 g/ton) group during the early part of the study but no adverse effects were observed on the health or well being of these animals. No adverse effects on weight gain and feed consumption were observed; nor were any significant treatment-related clinicopathologic, gross or histopathologic finding detected.

Dr. J. W. Pulliam, Study Director
Animal Science Research
Merck Research Laboratories
Rahway, NJ 07065

Tolerance Studies (ASR # 12297 and ASR # 11129)
Two tolerance studies were run, one in the U.S. (ASR # 12297) and the other in Germany (ASR # 11129), to assess the safety of efrotomycin in pigs when included in their ration continuously at levels up to 5 times (80 ppm/72.5 g/ton) the highest recommended level for 90 days (U.S.), or up to 20 times (320 ppm/290 g/ton) the highest recommended level for 28 days (Germany).

ASR # 11297
Sixteen castrated male and an equal number of female, individually identified 5-week-old crossbred swine, were assigned randomly to four treatment groups and housed individually. The pigs were fed a single basal ration that contained the premix carrier, efrotomycin at 16 ppm (14.5 g/ton), efrotomycin at 48 ppm (435 g/ton) or efrotomycin at 80 ppm (72.5 g/ton) continuously for 112 days. Weight gain, feed consumption and clinical health during the study were recorded. Blood was collected periodically for clinicopathologic evaluation. One replicate of each sex was randomly selected for necropsy, gross and histopathologic evaluation on Days 56 and 112. No adverse treatment-related effects were observed during the study or during histopathologic evaluation.

Dr. D. H. Wallace, Study Director
Merck Research Farm
Merck Research Laboratories
Fulton, MO 65251

ASR # 11129
A similar study was conducted in 8-week-old German Landrace pigs in Germany. The animals were housed individually and fed a single basal ration that contained the premix carrier only, or efrotomycin at 16 (14.5 g/ton), 80 (72.5 g/ton), 160 (145 g/ton), or 320 ppm (290 g/ton) for 28 days. Weight gain, feed consumption, and clinical health were recorded during the study. No adverse reactions were observed during the study, nor were weight gain or feed consumption adversely affected by the treatments.

Dr. D. Barth, Study Director
Merck Research Laboratories
Kathrinenhof
8201 Lauterback, W. Germany

Reproductive Study in Gilts (ASR # 11241)
This study was conducted to assess the influence of efrotomycin on the reproduction potential of gilts. Thirty-two, Yorkshire-cross 11 week-old gilts were allocated randomly into two treatment groups. The pigs had free access to water and an appropriate ration from 11 weeks of age for 112 days. Efrotomycin at 16 ppm (14.5 g/ton) was included in the ration of the medicated treatment group for the 112-day grow-out period but was not included in the ration during the remainder of the study.

When the gilts were sexually mature, one boar was randomly allocated to a pen block of four gilts. Each gilt was bred to its allocated boar, observed for return to estrus, and checked for pregnancy during the gestation period. The piglets were weighed at parturition, and at 7 and 21 days of age. Deaths and abnormalities were recorded for each litter.

Three gilts (2 nonmedicated control and 1 medicated) were euthanized during gestation because of traumatic injury and recumbency. No significant differences were observed between treatment groups with regard to percentage of gilts conceiving during first breeding cycle or percentage of gilts farrowing. No adverse effect was observed on the size and weight of litters at birth, 7 or 21 days of age.

Dr. D. H. Wallace, Study Director
Merck Research Farm
Merck Research Laboratories
Fulton, MO 65251

 

VI. Human Food Safety:
  1. Toxicity Tests:

    1. Two Generation Dietary Reproduction Study in Rats

      Report Number: TT #85-9016.

      Starting Date: 6/18/85

      Termination Date: 7/19/86.

      Responsible Investigator:

      Alan M. Hoberman, Ph.D.
      Argus Research Laboratories, Inc.
      Horsham, PA 19044.

      Laboratory:

      Argus Research Laboratories, Inc.
      Horsham, PA 19044

      Substance and Dosage Form Tested: Efrotomycin (L-628,313) mixed in the diet.

      Species and Strain: Crl:CD(SD)BR rats.

      Number of Animals/Sex/Group: 30 (F0); 25 (F1b).

      Dose Levels and Duration of Dosing:

      0.1, 0.33, and 1.0% of the diet (corresponding to drug intake levels of approximately 60, 200, and 600 mg/kg/day for males and 75, 230, and 700 mg/kg/day for females, respectively) prior to mating and throughout the production of F1 and F2 generations with two litters per generation.

      Routes of Administration: Oral via the diet.

      Parameters Examined:

      Daily clinical signs, body weight and food consumption, mating incidence, and fertility and gestation indices; offspring were evaluated at birth for gross external abnormalities. Necropsies were performed on all F0 and F1b animals and selected offspring from F1b, F2a and F2b litters.

      Toxicity Observed:

      Slight decreases in body weight gain and food consumption were found among the 1.0% dose group F0 males and the 0.33 and 1.0% dose group F0 females. Similar decreases in body weight gain at weaning were found among the offspring in the F1a through F2b 1.0% dose group litters. Thereafter, body weight gains in the affected groups were similar to controls, suggesting the earlier observed effects were due to initial taste aversion to the medicated diets containing the higher concentrations of efrotomycin. No other treatment-related effects were observed during the study.

    2. Unscheduled DNA Synthesis in Rat Hepatocytes

      Report Number: TT #83-8306

      Starting Date: 4/12/83.

      Termination Date: 5/13/83.

      Responsible Investigator:

      John G. Deluca, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486

      Substance and Dosage Form Tested: Efrotomycin (L-628,313) dissolved in dimethyl sulfoxide.

      Species and Strain: Primary hepatocyte cultures derived from a male Crl:CD(SD) BR rat.

      Dose Levels Tested: 0.2 to 2,000 mcg/ml.

      Results:

      Efrotomycin did not induce unscheduled DNA synthesis in this autoradiographic assay based on comparable grain area in treated and negative control cultures. The positive control agent, dimethylnitrosamine, gave the expected positive response.

    3. V-79 Mammalian Cell Mutagenesis Assay

      Report Number: TT #83-8512.

      Starting Date: 5/11/83.

      Termination Date: 6/13/83.

      Responsible Investigator:

      Matthews O. Bradley, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486

      Substance and Dosage Form Tested: Efrotomycin (L-628,313; Batch C34) dissolved in dimethyl sulfoxide.

      Species and Strain: V-79 Chinese hamster lung cells.

      Dose Levels Tested: 0.01 to 0.3 mM with S-9; 0.1 to 0.4 mM without S-9.

      Results:

      No evidence of mutagenicity was found in cultures treated with efrotomycin in the presence of S-9 activation. However, without S-9 activation increases in mutation frequency up to approximately 15-fold of the concurrent negative control were found. These results were considered of questionable significance in view of the lack of a dose- response relationship, precipitation of drug at the two highest concentrations tested resulting in marked cytotoxicity, and unusually low concurrent negative control mutation frequency in comparison to historical control values. Therefore, repeat studies were conducted (see TT #83-8518 and Tt #83-8524 below).

    4. V-79 Mammalian Cell Mutagenesis Assay

      Report Number: TT #83-8518.

      Starting Date: 6/22/83.

      Termination Date: 7/6/83.

      Responsible Investigator:

      Matthews O. Bradley, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486

      Substance and Dosage Form Tested: Efrotomycin (L-628,313; Batch C34 dissolved in dimethyl sulfoxide.

      Species and Strain: V-79 Chinese hamster lung cells.

      Dose Levels Tested: 0.03 to 0.2 mM without S-9.

      Results:

      There were no 3-fold or greater increases in mutation frequency in the treated cultures as compared to the concurrent negative controls. Therefore, efrotomycin is considered negative in this assay. The positive control agent, methyl nitrosourea (500 uM), without S-9 gave the expected increase in mutation frequency.

    5. V-79 Mammalian Cell Mutagenesis Assay

      Report Number: TT #83-8524.

      Starting Date: 8/17/83.

      Termination Date: 9/8/93.

      Responsible Investigator:

      Matthews O. Bradley, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486

      Substance and Dosage Form Tested: Efrotomycin (L-628,313; Batch C41) dissolved in dimethyl sulfoxide.

      Species and Strain: V-79 Chinese hamster lung cells.

      Dose Levels Tested: 0.04 to 0.40 mM without S-9.

      Results:

      No 3-fold or greater increase in mutation frequency was found in any of the treated cultures as compared to the concurrent negative control group. The positive control compound, dimethyl nitrosourea (500 uM), without S-9 gave the expected positive response. Therefore, retesting of the lot of efrotomycin which gave the initial increase in mutation frequency as well as a new lot of material failed to confirm the positive response, indicating that efrotomycin is not mutagenic in this assay.

    6. 14-Week Oral Toxicity Study in Dogs

      Report Number: TT #77-020-0.

      Starting Date: 5/16/77.

      Termination Date: 8/17/77.

      Responsible Investigator:

      Ken Norbury, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486

      Substance and Dosage Form Tested: Efrotomycin (L-628,313) in aqueous suspension.

      Species and Strain Used: Beagle Dogs.

      Age Range and Study Initiation: 50-60 weeks.

      Number of Animals/Sex/Group: 3.

      Dosage Levels and Duration of Dosing: 20, 200, and 2,000 mg/kg/day administered b.i.d. for 14 weeks.

      Route of Administration: Oral via gavage.

      Parameters Examined:

      Daily clinical appearance; body weights recorded twice weekly with routine ECG, hematologic, serum biochemical, and urinalysis studies performed in Drug Weeks 4, 8, and 12. Ophthalmology performed in Drug Weeks 4, 7, and 13. Complete necropsy on all dogs and extensive histopathological examination on all high dose and control animals.

      Toxicity Observed:

      Emesis and ptyalism in the high dosage group. Elevated serum alkaline phosphatase activities in all groups. Postmortem findings included increased absolute and relative liver weights in the 200 and 2,000 mg/kg/day groups without accompanying histomorphologic changes. Treatment-related microscopic findings were limited to the kidneys of the high dose group animals and included cortical scarring, tubular dilatation and papillitis.

      No-Observed-Effect Level: None.

    7. 14-Week Oral Toxicity Study in Dogs

      Report Number: TT #77-062-0.

      Starting Date: 10/10/77.

      Termination Date: 1/10/78.

      Responsible Investigator:

      Ken Norbury, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486.

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486.

      Substance and Dosage Form Tested: Efrotomycin (L-628,313) in aqueous suspension.

      Species and Strain Used: Beagle dogs.

      Age Range at Study Initiation: 53-60 weeks.

      Number of Animals/Sex/Group: 3.

      Dosage Levels and Duration of Dosing: 1, 2.5, 5, and 10 mg/kg b.i.d. for 14 weeks.

      Route of Administration: Oral via gavage.

      Parameters Examined:

      Daily clinical signs; body weights twice weekly with ECG's recorded in Drug Weeks 4, 8, and 13. Ophthalmoscopic examinations conducted in Drug Weeks 3, 5, 9, and 13. Hematologic, serum biochemical, and urinalysis studies were performed in Drug Weeks 4, 8, and 12. Complete necropsies were performed in all animals and extensive histopathological examinations conducted on all high dose and control dogs.

      Toxicity Observed: None.

      No-Observed-Effect level: 10 mg/kg b.i.d.

    8. Teratogenic Evaluation in Rats

      Report Number: TT #76-722-0.

      Starting Date: 9/6/76.

      Termination Date: 9/27/76.

      Responsible Investigator:

      Richard T. Robertson, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486.

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486.

      Substance and dosage Form Tested: Efrotomycin (L-628,313) in aqueous suspension.

      Species and Strain: Crl:CD(SD) BR rats.

      Number of Animals/Sex/Group: 20 females.

      Dose Levels and Duration of Dosing: 20, 200, and 2,000 mg/kg/day administered b.i.d. from Days 6 through 15 of gestation.

      Route of Administration: Oral via gavage.

      Parameters Examined:

      Daily clinical appearance, maternal and fetal body weights, numbers of implants, resorptions, live and dead fetuses at cesarean section; external, visceral, and skeletal examination of fetuses.

      Toxicity Observed:

      A treatment-related decrease in average fetal weight per litter was found in the 2,000 mg/kg/day dose group. No other compound-related effects were observed.

      No-Observed-Effect level: Maternotoxicity - 2,000 mg/kg/day; fetotoxicity - 200 mg/kg/day.

    9. Teratogenic Evaluation in Mice

      Report Number: TT #76-706-0.

      Starting Date: 3/4/76.

      Termination Date: 5/21/76.

      Responsible Investigator:

      Richard T. Robertson, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486.

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486.

      Substance and Dosage Form Tested: Efrotomycin (L-628,313) in aqueous suspension.

      Species and Strain: CF1S mice.

      Number of Animals/Sex/Group: 20 females.

      Dose Levels and Duration of Dosing: 20, 200, and 2,000 mg/kg/day from Days 6 through 15 of gestation.

      Route of Administration: Oral via gavage.

      Parameters Examined:

      Daily clinical appearance, maternal and fetal body weights, numbers of implants, resorptions, live and dead fetuses at cesarean section; external, visceral, and skeletal examination of fetuses.

      Toxicity Observed:

      There was no evidence of a teratogenic effect. There was a significant (P < 0.05) decrease in mean fetal weight per litter in the 2,000 mg/kg/day group. Fetotoxicity was evidenced by an increased incidence of incomplete ossification of the supraoccipitals and variations of the sternebrae, all in the high dose group. Two females from the 2,000 mg/kg group were observed to have a folded retina in the left eye. No other adverse effects were found.

      No-Observed-Effect Level: Maternotoxicity - 2,000 mg/kg/day; fetotoxicity - 200 mg/kg/day.

    10. Teratogenic Evaluation in Mice

      Report Number: TT #76-706-2.

      Starting Date: 4/15/76.

      Termination Date: 5/21/76.

      Responsible Investigator:

      James W. Noveroske, Ph.D.
      Merck Research Laboratories
      West Point, PA 19486.

      Laboratory:

      Merck Research Laboratories
      West Point, PA 19486.

      Substance and Dosage Form Tested: Efrotomycin (L-628,313) in aqueous suspension.

      Species and Strain: CF1S mice.

      Number of Animals/Sex/Group: 15 females.

      Dose Levels and Duration of Dosing: 20, 200, 1,000 and 2,000 mg/kg/day from Days 6 through 15 of gestation.

      Route of Administration: Oral via gavage.

      Parameters Examined:

      Daily clinical appearance, maternal and fetal body weights, numbers of implants, resorptions, live and dead fetuses at cesarean section; external, visceral, and skeletal examination of fetuses.

      Toxicity Observed:

      No evidence of maternotoxicity, fetotoxicity, or teratogenesis in any of the treated groups. The finding of a folded retina in the eye of one fetus in the 20 mg/kg/day group was considered unrelated to treatment, since this malformation was not found in any fetuses from the higher dose groups. Therefore, the folded retinal malformations and skeletal variations observed in the previous teratogenicity study in mice (TT #76-706-0) were not confirmed in this study and are, therefore, considered unrelated to drug treatment.

      No-Observed-Effect Level:

      0.1% in the diet corresponding to drug intake, levels of approximately 60 and 75 mg/kg/day in males and females, respectively.

    11. 14-Week Dietary Range-Finding Study in Mice

      Report Number: TT #85-9001.

      Starting Date: 1/2/85.

      Termination Date: 4/4/85.

      Responsible Investigator:

      E. Crosby Thompkins, Ph.D.

      Laboratory:

      Toxicity Research Laboratories
      Muskegon, MI 49444

      Substance and Dosage Form Tested: Efrotomycin (MK-0621; L-628,313) mixed in the diet.

      Species and Strain: Crl:CD-1 (ICR) BR mice.

      Number of Animals/Sex/Group: 15.

      Dose Levels and Duration of Dosing:

      0.5, 1.0, 2.0, and 5.0% of the diet (corresponding to drug intake levels of approximately 860, 1720, 3400, and 9370 mg/kg/day in males and 1040, 2000, 4320, and 10,640 mg/kg/day in females, respectively) for 14 weeks.

      Route of Administration: Oral via the diet.

      Parameters Examined:

      Daily clinical appearance, food consumption, and body weight. Complete necropsies and histopathologic examination of the kidneys were performed on all animals.

      Toxicity Observed:

      An increased incidence of glomerulonephritis and renal tubular cell regeneration was observed in the 2.0% and the 5.0% group males and females.

      No-Observed-Effect Level:

      1.0% in the diet corresponding to drug intake levels of approximately 1720 and 2000 mg/kg/day in males and females, respectively.

    12. 94-Week Dietary Carcinogenicity Study in Mice

      Report Number: TT #85-9015.

      Starting Date: 6/25/85.

      Termination Date: 4/10/87.

      Responsible Investigator:

      Bobby Joe Payne, D.V.M., Ph.D.

      Laboratory:

      Toxicity Research Laboratories
      Muskegon, MI 49444.

      Substance and Dosage Form Tested: Efrotomycin (MK-0621; L-628,313) mixed in the diet.

      Species and Strain: Crl:CD-1 (ICR) BR mice.

      Number of Animals/Sex/Group: 50.

      Dose Levels and Duration of Dosing:

      0.1, 0.33, or 1.0% of the diet (corresponding to drug intake levels of approximately 150, 500, and 1500 mg/kg/day, respectively) were fed continuously for 94 weeks.

      Route of Administration: Oral via the diet.

      Parameters Examined:

      Daily clinical signs, body weight and food consumption, palpable masses, and ophthalmology. Complete necropsies and histopathologic examinations were conducted on all animals.

      Toxicity Observed:

      A slight but statistically significant (P < 0.05) increase in mortality occurred in the high dose males only. This increase became evident in about Drug Week 50 and persisted for the duration of the study. There was a marked increase in the incidence of chronic nephritis in the high dose males and females only. No increases in tumor incidence were found at any dosage level.

      No-Observed-Effect Level:

      0.33% in the diet corresponding to a drug intake level of about 500 mg/kg/day.

    13. 14-Week Dietary Range-Finding Toxicity Study in Rats

      Report Number: TT #85-9002.

      Starting Date: 1/17/85.

      Termination Date: 4/19/85.

      Responsible Investigator:

      E. Crosby Thompkins, Ph.D.

      Laboratory:

      Toxicity Research Laboratories
      Muskegon, MI 49444.

      Substance and Dosage Form Tested: Efrotomycin (MK-0621; L-628,313) mixed in the diet.

      Species and Strain: Crl:CD(SD) BR rats.

      Number of Animals/Sex/Group: 15.

      Dose Levels and Duration of Dosing:

      0.5, 1.0, 2.0, and 5.0% of the diet (corresponding to drug intake levels of approximately 360, 710, 1440, and 3790 mg/kg/day and 400, 810, 1645, and 4300 mg/kg/day for males and females, respectively) for 14 weeks.

      Route of Administration: Oral via the diet.

      Parameters Examined:

      Daily clinical appearance, food consumption, body weight, and serum biochemistry. Complete necropsies and histopathologic examination of the kidneys were performed on all animals.

      Toxicity Observed:

      An increased incidence of glomerulonephritis and renal tubular cell regeneration was observed in the 2.0% group males and the 5.0% group males and females.

      No-Observed-Effect Level:

      1.0% in the diet corresponding to drug intake levels of approximately 710 and 810 mg/kg/day in males and females, respectively.

    14. 105-Week Dietary Carcinogenicity/Toxicity Study in Rats with a 53-Week Interim Sacrifice

      Report Number: TT #85-9014.

      Starting Date: 6/18/85.

      Termination Date: 6/17/85 (Interim Sacrifice) 6/15/87 (Terminal Sacrifice)

      Responsible Investigator:

      Bobby Joe Payne, D.V.M., Ph.D.

      Laboratory:

      Toxicity Research Laboratories
      uskegon, MI 49444

      Substance and Dosage Form Tested: Efrotomycin (MK-0621; L-628,313) mixed in the diet.

      Species and Strain: Crl:CD(SD) BR rats.

      Number of Animals/Sex/Group: 65 (15 for 1-year interim sacrifice).

      Dose Levels and Duration of Dosing:

      0.1, 0.33, or 1.0% of the diet (corresponding to drug intake levels of approximately 43, 146, and 450 mg/kg/day and 55, 178, and 570 mg/kg/day for males and females, respectively) for either 53 weeks (interim sacrifice) or 105 weeks (terminal sacrifice).

      Route of Administration: Oral via the diet.

      Parameters Examined:

      Daily clinical signs, body weight, feed consumption, ophthalmology, hematology, serum biochemistry, urinalysis, and palpable masses. Complete necropsies and histopathologic examination were performed on all terminal necropsy animals.

      Toxicity Observed:

      A statistically significant decrease (P < 0.05) of about 20% in body weight gain was found in the high dose females only compared to controls at termination. There was an increase in the incidence of chronic nephritis in the mid and high dose group females at the terminal but not the interim necropsy. No other treatment-related microscopic changes were found and no increase in tumor incidence at any site was found at any dosage level.

      No-Observed-Effect Level:

      0.1% in the diet corresponding to drug intake levels of approximately 43 and 55 mg/kg/day in males and females, respectively.

  2. Safe Concentration of Residues

    The no-observed-effect level (NOEL) of 10 mg/kg/day from the 14-week oral toxicity study in dogs was used to determine the safe residue concentration in foods using a 1,000-fold safety factor. Based on the above, the acceptable daily intake of efrotomycin is 0.6 mg/day.

    i.e.,

    10 mg/kg/day ÷ 1000 safety factor = 0.01 mg/kg/day
    0.01 mg/kg/day x 60 kg = 0.6 mg/day

    To establish a safe residue concentration in the five major edible tissues of swine the relative tissue consumption of each tissue must be considered based on information provided in the "Working Guidelines for Assigning Residue Tolerances", September 1986, prepared by: Food Animal Additives Branch (HF-180), Division of Toxicology, Bureau of Foods, Food and Drug Administration. These relative tissue consumption values based upon the consumption of 500 grams of meat per day by a 60 kg individual are as follows:

    • Kidney 0.25
    • Fat 0.25
    • Liver 0.33
    • Muscle 1.0
    • Skin 0.25

    Therefore, the safe residue concentration in muscle, using a tissue consumption factor of 1.0, can be calculated as follows:

    0.6 mg/day ÷ 500 grams/day = 1.2 ppm

    Based upon the above relative tissue consumption factors, the safe residue concentrations in the remaining edible tissues are obtained as follows:

    • Liver 1.2 ppm ÷ 0.33 = 3.6 ppm
    • Kidney 1.2 ppm ÷ 0.25 = 4.8 ppm
    • Skin 1.2 ppm ÷ 0.25 = 4.8 ppm
    • Fat 1.2 ppm ÷ 0.25 = 4.8 ppm
  3. Total Residue and Metabolism

    Efrotomycin consists of a mixture of isomers, the major of which are isomer A1 (65-75% of the drug) and two B isomers (10-25% of the drug). The levels of total drug-related residues of efrotomycin (EFM) in the tissues of swine treated with 14C-efrotomycin were determined in a study conducted by Merck Research Laboratories. The study involved administration of only the 14C-labeled A1 isomer with the exception that A1 would be converted to the B isomers in vivo. This prediction was borne out by the metabolism data, as discussed below.

    Dose: 16 ppm of 14C-labeled efrotomycin isomer A1 in the feed for seven days.

    Test Animals: 12 domestic crossbred swine (6 male, 6 female); initial age, about 11-14 weeks, initial weight, 15-23 kg.

    Withdrawal schedule:

    Three animals were slaughtered immediately after withdrawal of the drug (zero hours withdrawal) and three animals at each of 8, 24 and 48 hours after withdrawal of the drug.

    Samples of muscle, liver, kidney and fat from each animal were radioassayed by combustion of the sample, trapping the resulting 14CO2, and liquid scintillation counting. The results from this study are presented in the following table.

    TOTAL RADIOACTIVITY (PMM ± STANDARD DEVIATION) IN EDIBLE TISSUES OF SWINE FED 14C-LABELED EFROTOMYCIN AT 16 PPM IN FEED FOR SEVEN DAYS.

    Withdrawal Period Liver Kidney Muscle Fat None (on drug) 0.160 ± 0.029 0.040 ± 0.009 0.011 ± 0.003 NDb 8 hr 0.140 ± 0.030 0.043 ± 0.015 0.009 ± 0.004 0.010 ± 0.009 24 hr 0.084 ± 0.016 0.022 ± 0.007 ND(a) ND(b) 48 hr 0.013 ± 0.002 0.013 ± 0.005 ND(a) ND(b) ND = not detected (a) = detection limit of 0.005 ppm (b) = detection limit of 0.01 ppm

    Livers from swine in the residue study described above were subjected to analytical procedures to establish the profile of 14C-efrotomycin metabolites present. The approach involved solvent extractions followed by reversed-phase high performance liquid chromatography (HPLC) and reverse isotope dilution assay. Several extraction procedures were used, which varied in the extraction solvent and whether the samples were pretreated by lyophilization.

    The HPLC profiles indicated that there were five main components of efrotomycin residue in livers from swine slaughtered while on the drug. The primary component was unchanged isomer A1, representing 33-47% of the residue. Two peaks that were more polar than isomer A1 constituted 14-42% (polar peak 1) and 16-21% (polar peak 2) of the residue. The region of the HPLC profile in which compounds less polar than A1 would elute, the "post A1" region, consisted of many small peaks, which together accounted for 6-12% of the residue. In addition, 3-10% of the residue eluted when the HPLC column was washed with methanol.

    Metabolic profiles were also determined in the livers and excreta of rats of the same strain used in efrotomycin toxicological testing. This study showed the presence of polar peaks 1 and 2 and isomer A1 in rat liver. Overall, the study indicated that the rats had been exposed to the metabolites that collectively comprise approximately 90% of the metabolites present in swine liver HPLC profiles.

    Additional metabolism work showed that the B isomers were present in feces of both swine and rats from the comparative metabolism study. There results substantiated the conclusion that a portion of isomer A1 is converted to the B isomers in vivo. The results also demonstrate that the swine in the total residue study and the rats in the comparative metabolism study were both exposed to the B isomers.

    Preliminary evidence suggest that some of the components of polar peak 2 might be isomers of efrotomycin. Because the amount of total residue in swine is low, relative to the safe concentration, and the toxicological potential of the metabolites is low, definitive identification of the metabolites was not required.

  4. Withdrawal Period

    Because the total residues of efrotomycin were well below the safe concentrations in all edible tissues in swine, a zero-day withdrawal period has been granted for use of efrotomycin in swine feed at up to 16 ppm (14.5 g/ton). For this reason, a target tissue, marker residue and tolerance have not been assigned for this use of efrotomycin.

  5. Regulatory Method

    A regulatory method is not required for this use of efrotomycin because the toxicology and residue data support a zero-day withdrawal.

  6. Microbiological Safety

    1. Coliform Resistance:
      A study was conducted to determine if efrotomycin would have an effect on the incidence of antimicrobial resistance in enteric coliforms (Escherichia coli). E. coli sensitivity to 12 commonly used antibiotics was determined by the standard disc test (Bauer-Kirby). After an eight-week period during which pigs were fed a ration that contained efrotomycin at 16 ppm (14.5 g/ton), there was no significant change in sensitivity patterns of E. coli population to the 12 antibiotics used in the test. Efrotomycin did not affect antibiotic resistance in these studies.
    2. Effect on Salmonella typhimurium shedding:
      Two studies were conducted to assess whether use of 16 ppm (14.5 g/ton) efrotomycin in swine feed increases Salmonella shedding and/or antimicrobial resistance of Salmonella. The assessment considered quantity of Salmonella shed, prevalence and duration of shedding, tissue sequestering of Salmonella and antimicrobial susceptibility to 12 antimicrobial drugs. Each study used 20 pigs which were 7-8 weeks old when orally inoculated with S. typhimurium. Half of the pigs were randomly allocated to be fed a basal ration that included efrotomycin at 16 ppm (14.5 g/ton), while the others were fed the basal ration plus placebo (premix carrier). All pigs were individually housed with the medicated and non-medicated pigs in separate but identical rooms. Fecal samples were collected at intervals during 56 days of medication and examined for S. typhimurium. Individual isolates of Salmonella were tested for their susceptibility to 12 antimicrobial drugs. Tissue samples, collected at the end of each study, were examined for the presence of Salmonella.

      It was concluded that use of efrotomycin in swine feed at up to 16 ppm (14.5 g/ton) does not increase Salmonella shedding or affect antimicrobial susceptibility of Salmonella, nor tissue sequestering of Salmonella.

VII. Agency Conclusions:

The animal safety and efficacy data submitted in support of this NADA satisfy the requirements of Section 512 of the Act. The effectiveness data demonstrate that efrotomycin included in the feed from 2 to 16 ppm (1.8 to 14.5 g/ton) for increase rate of weight gain and from 2 to 4 ppm (1.8 to 3.6 g/ton) for improved feed efficiency is efficacious. The sponsor has elected to label for the range of 4 to 16 ppm (3.6 to 14.5 g/ton) for increased rate of weight gain, and a point approval of 4 ppm (3.6 g/ton) for improved feed efficiency.

Six dose-titration/confirmation studies were conducted, according to one protocol, at five different locations by five different investigators. A minimum of four replicates of five treatment groups with 4-6 pigs per pen was used in each study. These studies included a total of 29 replicates, using a total of 140 pigs for each treatment group. The pigs were fed efrotomycin at 0, 2 (1.8 g/ton), 4 (3.6 g/ton), 8 (7.3 g/ton), and 16 ppm (14.5 g/ton) in commercial rations continuously over a 112- to 128-day grow-out period. The pigs were weighed individually at the time of allocation, at least once each 28-day interval during the course of each study, and at termination of each study. Ration changes were generally coordinated with the regular weighings of the pigs. Any pigs that died during the course of a study were necropsied and subjected to pertinent laboratory tests to determine probable cause of death. The studies were terminated when the heaviest group of pigs reached market weight, an average of 120 days duration. All pigs in a study were given their final weighing on the same day.

A significant (P < 0.10) linear dose response in rate of weight gain throughout the range of inclusion levels of efrotomycin was observed through the complete test period. Percentage increases above the nonmedicated controls for rate of weight gain were 5.9% at 2 ppm (1.8 g/ton) and 8.9% at 16 ppm (14.5 g/ton). These data show that the effective range of inclusion levels of efrotomycin for increased rate of weight gain is 2 to 16 ppm (1.8 to 14.5 g/ton). Linear plateau analysis of feed efficiency data showed a significant (P < 0.05) linear dose response up to 4 ppm (3.6 g/ton) level of efrotomycin. The percentage increases above control ranged from 1.7% at 2 ppm (1.8 g/ton) to 4.0% at 4 ppm (3.6 g/ton). The results show that the effective range of inclusion levels of efrotomycin for improvement in feed efficiency is 2 (1.8 g/ton) to 4 ppm (3.6 g/ton).

The safety of efrotomycin when used at the recommended use levels has been demonstrated in several range finding and dose titration studies. Additional studies were run to show that efrotomycin can be fed to pigs at greater than recommended use levels to demonstrate adequate safety margin. In the Acute Toxicity study, semi-solid and perianal erythema were seen on a transient basis in some pigs in the 400 ppm (362.5 g/ton) group during the early part of the study. But, no adverse effects were observed on the health and well being of these animals. No treatment related clinicopathologic, gross or histopathologic findings were detected in this study. No adverse effects were observed for weight gain and feed consumption in the Acute Toxicity or Tolerance studies. No adverse treatment related effects were observed during the Tolerance studies or during histopathologic evaluation. In the Gilt Reproductive study, no adverse effects were observed for size and weight of litters at birth, 7 or 21 days of age, and percentage of gilts conceiving or percentage of gilts farrowing. The drug is to be fed in Type B and Type C Medicated feeds, in accordance with Section 2 and 3 of the FOI Summary and the Blue Bird labeling that is attached to this document.

Two studies were conducted to assess whether use of 16 ppm (14.5 g/ton) efrotomycin in swine feed increases Salmonella shedding and/or antimicrobial resistance of Salmonella. The assessment considered quantity of Salmonella shed, prevalence and duration of shedding, tissue sequestering of Salmonella and antimicrobial susceptibility to 12 antimicrobial drugs. Each study used 20 pigs which were 7-8 weeks old when orally inoculated with S. typhimurium. It was concluded that use of efrotomycin in swine feed at up to 16 ppm (14.5 g/ton) does not increase Salmonella shedding or affect antimicrobial susceptibility of Salmonella, nor tissue sequestering of Salmonella.

Merck's studies showed that if the drug is used in accordance with the label directions, unsafe levels of efrotomycin residues should not be present in edible swine tissues. For this reason, a target tissue, marker residue, tolerance, and analytical method for residues are not required.

Section 512(c)(2)(F)(i) of the Federal Food, Drug and Cosmetic Act provides a five-year period of exclusivity to NADAs because no active ingredient (including any ester or salt thereof) has been previously approved in any other NADA filed under section 512(b)(1) of the Act. This NADA qualifies for such an exclusivity period which will expire five years from the date of the approval letter.

Producil is categorized for over-the-counter use. Adequate directions can be written for use of this drug product by laypersons within the swine industry. Further, there is no special need to recognize a disease condition since Producil is intended for use only for increased rate of weight gain and improved feed efficiency, the drug is not a "controlled substance," and after feeding there is no need for medical monitoring or evaluation of treated animals.

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