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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 096-298 Bovatec® - original approval

I. GENERAL INFORMATION:

NADA 096-298
Sponsor: Hoffmann-LaRoche, Inc.
Nutley, New Jersey 07110
Generic Name: lasalocid
Trade Name: Bovatec®
Marketing Status:  

2. Indication for Use

For increased rate of gain and for improved feed efficiency in beef cattle fed in confinement for slaughter.

3. Dosage Forms

Medicated Premix Concentrations of 15%, 20%, 33%, and 50% are available.

Dosage and Administration

To be fed to beef cattle in confinement for slaughter at a rate of 10-30 grams/ton for improved feed efficiency and 25-30 grams/ton for increased rate of weight gain with a zero day withdrawal.

4. Summary of Efficacy Data

Sixteen well-controlled, replicated, titration studies determining dose-response efficacy, all including negative control and usually positive control, were conducted in feedlots under commercial conditions. A total of over 2000 cattle used in these tests were run in California, Colorado, Florida, Illinois, Kansas and Texas, efficiency and rate of gain. A weighted, pooled, statistical analysis of the 16 studies indicates the addition of lasalocid (lasalocid soduim and lasalocid biomass) resulted in an improvement in feed efficiency at a level of 10 to 30 g/ton and an increased rate of weight gain at 25-30 g/ton. Details and results of the individual studies follow.

Study 773

This trial was conducted by Dr. George V. Davis, Garden City Branch, Kansas Agricultural Experiment Station, Garden City, Kansas.

Steers with an average body weight of 304 kg were fed in confinement for 112 days a high energy ration supplemented with lasalocid sodium (11, 22, or 33 ppm). Two treatments, a control and a lasalocid 33 ppm were fed urea as the main N source instead of cottonseed meal (CSM). There were 2 replicates per treatment. Results were as follows:

Ed. note:  The following table has 7 columns.

                                  Controls              Lasalocid Sodium
                                ____________     _______________________________     
                                                  11ppm   22ppm   33ppm   33ppm
                                 Urea   CSM        CSM     CSM     CSM    Urea
                         

 

Avg. daily gain kg 1.30 1.23 1.34 1.24 1.21 1.30 Avg. daily feed intake kg(a) 9.65 9.22 9.19 8.64 8.17 8.92 Feed/weight gain 7.44 7.53 6.85 6.97 7.31 6.89

 

(a) 90% dry matter

Study 777

This trial was conducted at the Texas Tech University Center at Amarillo, Texas by Dr. Wm. Mies, Pantex, Texas 79069

Steers with an average body weight of 318 kg were fed a high concentration ration of steam flaked sorghum grain supplemented with lasalocid sodium (11, 22, and 33 ppm) and compared to unmedicated control animals. The experimental period lasted 112 days. The trial simulated commercial feedlot conditions. There were 5 head per replicate, 2 replicates per treatment. Results were as follows:

Ed. note:  The following table has 5 columns.

                               Control               Lasalocid
                                            ____________________________
                                             11 ppm    22 ppm    33 ppm
                                             

 

Avg. daily gain 1.19 1.16 1.05 1.28 Avg. daily intake kg(a) 10.31 9.82 9.35 10.44 Feed/Gain 8.66 8.47 8.90 8.15 Rumen C3, Molar % 41.3 42.6 49.8 48.0

 

(a) 90% dry matter

Study 779

This trial was conducted by Dr. Dallas Horton, Fort Collins, Colorado.

Lasalocid sodium (22, 33, 44 and 55 ppm) was supplemented to feedlot steers (initial weight 345kg) receiving a high energy ration and to similarly supplemented unmedicated control animals, during 112 days under simulated commercial feedlot conditions. The average daily dry matter intake was significntly reduced when 22 and 44 ppm of lasalocid were supplemented as shown in the following chart.

Ed. note:  The following table has 6 columns.
                               Control             Lasalocid Sodium
                                          ___________________________________
                                           22 ppm   33 ppm   44 ppm   55 ppm
                                           

 

Avg. Daily Gain Kg 1.25 1.21 1.19 1.25 1.28 Avg. Daily Intake Kg(a) 9.94 9.38 9.52 9.41 9.50 Feed/Gain 7.93 7.76 8.02 7.47 7.41 Replicates/head 3/8 3/8 3/8 3/8 2/8

 

(a) 90% dry matter

Study 783

This trial was conducted at Santa Yenz, California by Dr. Jack Algeo.

Feedlot finishing steers (initial weight 281 kg) were fed a high energy ration supplemented with 0, 11, 22, 33, or 22 ppm of lasalocid soduim. Feed intake, body weight gains and feed efficiency were studied during the 124 days of the experimental period. The animals were managed simulating conditions of commercial feedlots. There were 8 cattle per replicate, 2 replicates per treatment. Results were as follows:

Ed. note:  The following table has 4 columns.


                     Average Daily    Average Daily Feed
                        Gain Kg          Intake(a) Kg         Intake/Gain

 

Control 1.17 9.29 7.97 Lasalocid 11 ppm 1.25 9.35 7.51 Lasalocid 22 ppm 1.20 9.31 7.77 Lasalocid 33 ppm 1.23 9.03 7.35 Lasalocid 44 ppm 1.16 8.95 7.69

 

(a) 90% Dry Matter (AFDI)

Study 793

This trial was conducted by Dr. W. Mies, Texas Tech University Center at Amarillo, at Pantex, Texas.

A 128 day trial was conducted with Hereford heifers (initial weight 313 kg) to study the effect of the supplementation of graded levels of lasalocid sodium in comparison to lasalocid biamass. There were 8 head per replicate, 4 replicates per treatment. The results were as follows:

Ed. note:  The following table has 6 columns.

                                     Lasalocid Sodium      Lasalocid Biomass
                                    __________________    ___________________
                        Control      10g/t      30g/t      45g/t       30g/t
                        

 

Avg. Daily Gain kg 1.25 1.26 1.31 1.20 1.21 ADFI, 90% DM, kg 10.90 10.78 11.20 10.65 10.19 F/G 8.73 8.55 8.58 8.94 8.52 C2:C3 1.07 1.10 1.11 1.00 0.99

 

Study 792

This trial was conducted by Dr. Richard Brown, Lamar, Colorado.

Steers (initial weight 227 kg ) were supplemented for 236 days with graded levels of lasalocid sodium and compared to lasalocid biomass, and replicates per treatment. Results were as follows:

Ed. note:  The following table has 7 columns.

                                        Lasalocid Sodium        Lasalocid Biomass
                                    _________________________
    g/ton                 Control    10     20     30     45           30
    

 

Avg. Daily Gain kg 1.01 1.01 1.10 1.09 1.10 1.11 Avg. Daily Intake(a) kg 9.21 9.01 9.04 8.74 8.87 9.01 Feed Conversion 9.12 8.89 8.25 8.02 8.09 8.10

 

(a) 90% Dry Matter

Study 789

This trial was conducted by Mr. John Brethour, Agricultural Experiment Station, Fort Hays Branch, Kansas State University, Hays, Kansas.

Yearling steers (initial weight 376 kg) were fed a high energy finishing ration supplemented with lasalocid 30 g/ton compared to unmedicated controls. There were 12 head per replicates, 2 replicates per treatment.

Lasalocid increased significantly the rate of gain and the conversion of feed into weight gain. Lasalocid improved hot dressing percentage and cutability score of the carcasses graded choice or better.

Ed. note:  The following table has 3 columns.

                               Control      Lasalocid
                               _______      _________
Avg. Daily Gain, kg             1.52          1.74
Avg. Daily Intake, kg          12.44         12.30
Food/Gain                       8.20          7.10

Study 791

This trial was conducted by Dr. George V. Davis, Garden City Branch, Kansas Agricultural Experiment Station, Kansas State University, Garden City, Kansas.

Lasalocid sodium was fed to steers (initial weight 308 kg) at concentrations of 0, 10, 20 and 45 g/ton in a high concentrate ration to finishing feedlot steers for 130 days, and it was compared to lasalocid biomass 45 g/ton. There were 8 head per replicate and 4 replicates per treatment.

Ed. note:  The following table has 6 columns.

                                Lasalocid Sodium       Lasalocid Biomass
                             _______________________   _________________
                    Control   10g/t   20g/t   45g/t         45g/t
                    

 

ADG, Kg 1.49 1.48 1.45 1.52 1.30 F.I., kg 90% DM 9.63 9.48 9.38 9.51 9.59 F/G 6.48 6.38 6.46 6.26 6.38 % Improvement - 1.54 0 3.40 1.54 A:P(a)-Ratio 1.09 1.03 1.02 0.99 1.06

 

(a) Rumen acetate to propionate ratio.

Study 803

This trial was conducted by Mr. John R. Brethour, Fort Hays Branch Agricultural Experiment Station, Kansas State University, Hays, Kansas.

Lasalocid was fed at a concentration of 30 g/ton to finishing feedlot steers, initial weight 381 kg. There were 2 replicates of 12 head each per treatment, one replicate was fed urea as the main nitrogen source and the other was fed soybean meal.

Ed. note:  The following table has 3 columns.

Test 110 days                               Lasalocid Sodium
                                            ________________
                               Control            30
                               

 

Avg. daily gain (kg) 1.61 1.80 % improvement 11.8 Avg. daily feed intake 13.79 13.39 (90% DM) (kg) Feed/gain 8.54 7.46 % Improvement 12.6

 

Study C-6

This trial was conducted by Dr. G. Pearl, Lexington, Illinois.

The effect of lasalocid was compared to controls in a 140 day feeding trial with finishing steers (initial weight 313 kg) fed a shelled corn diet. There were four replicates of 10 animals per treatment at a dose of 300 mg/head/day.

The animals were slaughtered after 14 days of drug withdrawal.

Ed. note:  The following table has 3 columns.


                                    Control            Lasalocid (300mg/hd/da)
                                    

 

Avg. Daily Gain, kg 1.24 1.30 Avg. Daily Feed Intake(a), kg 7.94 7.66 Avg. Feed/Gain Ratio 6.38 5.88

 

(a) 90% dry matter

Study C-23

This trial was conducted by Dr. Richard Johnson at the Southeast Kansas Agricultural Experiment Station, Parsons, Kansas.

Lasalocid sodium was supplemented to Hereford steers, initial weight 331 kg. at concentrations of 300 and 450 mg/head/day and compared to untreated controls in a 112 day finishing feedlot study. There was no significant difference between treatments in rate of gain, feed intake, feed conversion into weight gain and in carcass traits. There were 8 head per replicate; 3 replicates per treatment.

Ed. note:  The following table has 4 columns.

                                                      Lasalocid
                                            _____________________________
                               Control      300 mg/hd/da     450 mg/hd/da

Avg. daily gain(a), kg 1.52 1.58 1.58 Avg. daily feed intake(b) 90% dry matter, kg 11.89 12.56 12.48 Feed/gain(b), kg 8.90 9.21 9.09 Liver abscesses 7.2% 0 0

(a) days 1-112 (b) days 29-112

Study C-29 This trial was conducted by Dr. Larry Berger, Dept. of Animal Science, College of Agriculture, University of Illinois, at Urbana-Champaign.

Lasalocid sodium was fed at concentrations of 0, 30 and 45 g/ton and compared to controls in a Feedlot Finishing trial, using a completely randomized design of 3 treatments, 3 replicates per treatment, steers average initial weight 340 kg, per replicate. Results were as follows:

Ed. note:  The following table has 4 columns.

                                             Lasalocid sodium
                                             ________________
                               Control       30g/t      45g/t

ADG kg 0.99 1.02 1.02 AD Feed intake, 90% DM, kg 9.62 9.16 8.95 Feed/Gain 9.72 8.99 8.65 Improvement over control-% 7.51 11.00

SAFETY STUDY INFORMATION

Study C-10

This trial was conducted by Dr. Dallas Horton, Fort Collins, Colorado.

Steers and heifers (193 kg) were fed for 252 days on a growing diet (112 days) and finishing diet (140 days) supplemented with drug as noted in the following tables. Feed intake, body weight gains, and feed efficiency were studied during the growing, finishing, and combined growing-finishing periods. The animals were managed simulating conditions of a commercial feedlot. There were 8 head per replicate and 4 replicates per treatment.

Ed. note:  The following table has 5 columns.

Efficacy Study:   Treatments 1-6

Treatments                  # of pens    A.D.W.G. (kg)     A.D.F.I.(a)      F.C.

Control 4 1.09 9.13 8.43 Lasalocid 10 g/ton 4 1.06 8.91 8.41 Lasalocid 30 g/ton 4 1.10 8.77 8.02 Lasalocid 45 g/ton 4 1.05 8.50 8.10 Lasalocid 60 g/ton 4 1.07 8.40 7.90 Biomass 45 g/ton 4 1.08 8.59 7.94 S.E. of difference between any two means: 0.022 0.308 0.182

(a) Expressed as kg on a 90% dry matter basis.

Study C-29 This trial was conducted by Dr. Glyn M. J. Horton, Ona Research Station, Ona, Florida.

Steers (initial wt. 296 kg) were fed for 112 days on a high corn silage (72.8%) diet supplemented with drug as noted in the following tables. Animals were fed in pens of eight cattle with 4 pens per treatment, three treatments in the study. Feed intake, body weight gains, and feed efficiency were studied during the study. Three fecal collections were made during the trial and these were examined for coccidia oocysts. The animals were managed simulating conditions of a commercial feedlot.

Ed. note:  The following table has 4 columns.

The Effect of Lasalocid on Feedlot Performance on Steers

                                          Lasalocid        Lasalocid
Item                          Control     mg/kg/diet       mg/kg/diet

Dose of Drug                     0           33              49.5
No. of steers                   32           32              31
Initial Weight, kg             385          404             398
Avg. Daily Gain, kg              0.83         0.87            0.86
Percent of Control               -          116.6           103.9
Avg. Daily Feed
  Intake kg, 90% DM              9.43         9.49            9.39
Feed/Gain (ADFI/ADG)
  (using 90% DM on ADFI)        11.37         9.89           10.82

Study C-41

This trial was conducted by Dr. Richard Johnson, Southeast Kansas Agricultural Experiment Station, Parsons, Kansas.

Lasalocid was fed at 0 and 45 g/ton to confined Simmental cross steers (initial weight 377 kg) 7 per pen, 3 pens per treatment, running for 112 days on a concentrate (80%) and silage (20%) ration. The results are as follows:

Ed. note:  The following table has 3 columns.

Treatment                      Control          Lasalocid Only

ADG, Kg % Control 1.58 1.58 ADFI, Kg (90% DM) 13.25 11.70 % Control -11.7% Feed/Gain 8.40 7.38 % Improvement +12.1%

Study C-38

This trial was conducted by Dr. D. Horton at Wellington, Colorado.

Steers (initial weight 394 kg) were fed for 91 days on a high concentrate (80%) diet supplemented with drug as noted in the following tables. Animals were fed in pens of eight cattle with four pens per treatment.

Ed. note:  The following table has 6 columns.

Group   Treatment        Avg Daily    Avg Daily Feed    Feed    %Liver
number                   Gain, kg     Intake, kg(a)    Conver.  Abscess

1 Control 1.16 10.51 9.04 23.0 2 Lasalocid 45 g/t 1.18 9.63 8.15 34.4

(a)-Expressed on a 90% dry matter basis

5. Summary of Safety in the Animal

The safety of lasalocid in complete feeds both as sodium lasalocid and lasalocid biomass for the target species, cattle, was demonstrated by the long-term (252 days) feeding of graded levels of lasalocid of up to 5x the maximum approved feeding level.

Safety of Lasalocid in Cattle: Study C-10

Investigator: Dr. Dallas Horton, Fort Collins, Colorado

A target animal safety study was conducted alongside an efficacy feedlot study in heifers and steers using the crystalline lasalocid sodium and the lasalocid biomass at 150 g/t feed (5x the highest level) and 60 gm lasalocid sodium/ton (2x the highest level) for 252 days. The safety study utilized treatments 1,3,6,8 and 9 (lasalocid at 0, 30, 60, 150 and 150 lasalocid biomass g/t respectively): The only clinical signs of the 5x overdose was a transient diarrhea for 3 days after the 4th day of feeding. The cattle fed 60 g/t (2x highest dose) had no clinical symptoms of overdose. The results were as follows:

Ed. note:  The following table has 5 columns.

Treatments                 # of pens   A.D.W.G.(kg)    A.D.F.I.(a)     F.C.

Controls 4 1.09 9.13 8.43 Lasalocid 30 g/t 4 1.10 8.77 8.02 Lasalocid 60 g/t 4 1.07 8.40 7.90 Lasalocid 150 g/t 2 0.94 7.39 7.85 Biomass 150 g/t 2 0.92 7.12 7.17

(a) Expressed as kg on a 90% dry matter basis.

Additional Animal Safety Studies:

1. Commercial Supplements - A test was conducted to evaluate the acceptability and palatability of commercial type cattle supplements with two levels of lasalocid.

Cattle that had been acclimated to receiving 2.72 kg of ground corn meal daily were offered 0.91 kg of the test supplements medicated at the rate of either 1440 or 2880 gms of lasalocid per ton. Additional observations were made with a ground corn supplement medicated at 1200 g/ton.

When commercial type supplements containing various protein and mineral concentration and fortified with lasalocid were offered to confined cattle instead of their regular ration, the animals generally rejected the test supplements containing 1440 g and 2880 g lasalocid/90/kg. Only 12 animals out of 30 exposed to the test supplements had a lasalocid intake above 1 mg/kg bw. No visible effects from consuming the test supplements were observed in the test animals.

2. Lasalocid Premixes: Confined Feedlot Cattle

The effects of feeding the lasalocid premixes to confined, feedlot cattle are summarized below.

Ed. note:  The following table has 4 columns.

Exposure of Confined Feedlot Cattle to Lasalocid Premixes

                                No. Animals/Total Animals
 Lasalocid Premixes         ___________________________________
 (Concentration)            Rejected      Tasted       Consumed

13% 2/2 0/2 0/2 15% 3/4 1/4 0/4 20% 3/3 0/3 0/3 33% 2/2 0/2 0/2 50% 2/3 0/3 1/3

3. Lasalocid Premixes- Nonconfined Pasture Cattle:

Five steers were acclimated while on pasture to 0.45 kg of corn meal daily. They were offered one of the following lasalocid premixes; 13, 15, 20, 33, or 50%. Four of the five steers refused to eat the lasalocid premixes. One animal tasted the 13% lasalocid premix several times, but did not eat the premix.

4. Intermediate Feed Mill Premixes: Confined Feedlot Cattle

Studies were conducted to evaluate free-choice consumptionof the intermediate feed mill premixes with a finely ground corn meal carrier in the following concentrations.

10,000g/ton     11.0g lasalocid/kg feed
 5,000g/ton      5.5g lasalocid/kg feed
 2,500g/ton      2.75g lasalocid/kg feed
 1,200g/ton      1.32g lasalocid/kg feed

Generally, feedlot cattle readily consumed at least some of the intermediate lasalocid feed mill premix formulated with a corn meal carrier, the same ingredient as their daily feed.

Ed. note:  The following table has 5 columns.

                            No. Animals/Total Animals
Intermediate Feed Mill     ____________________________    Avg. Lasalocid
Premix-Lasalocid g/kg      Rejected   Consumed   Deaths   Intake, mg/kg bw

11.0 3/7 4/7 3/4 93-95 5.5 1/3 2/3 1/2 22-68 2.75 0/2 2/2 1/2 30-36 1.32 0/3 3/3 0/3 5.3-15.5

Of seven animals offered lasalocid in an intermediate lasalocid premix at a level of 11 g/kg of feed, three refused to eat: three animals died and one recovered after ingesting an intake of 93-95 mg/kg b.w. of lasalocid in a corn meal carrier.

Of three animals offered lasalocid intermediates at a level of 5.5 g/kg, one animal refused to eat, one animal ate an amount calculated to provide 22.2 mg/kg b.w. and survived. A third animal consumed this intermediate premix to achieve an intake of 68.7 mg/kg b.w. This animal died.

Of two animals ingesting the 2.75 g/kg intermediate premix, one survived a calculated 30.5 mg/kg ingestion rate. The other succumbed at a level of 35.8 mg/kg of b.w.

Of three animals offered lasalocid in an intermediate premix at a level of 1.32 g/kg of feed three animals ate up to 15.5 mg/kg b.w., causing no deaths of animals.

This study demonstrates that deaths can occur at the level of about 35 mg/kg b.w. Acceptability of lasalocid mixed with a ground corn meal carrier was also shown.

5. Intermediate Feed Mill Premixes: Non-confined Pasture Cattle

Six yearling steers on pasture were acclimated to 0.45 kg of corn meal daily. Instead of their daily feeding of corn meal, they were offered 0.45 kg of an intermediate feed mill premix containing 11 g, 5.5 g or 2.75 g lasalocid/kg for three consecutive days with the following consumption patterns:

Comment: The cattle consumed a range of 2.3- up to 22.4 mg/kg b.w. No clinical responses were reported.

6. Kansas State University- Synopsis of the morbidity and mortality of the Toxic Syndrom of Bovatec in Cattle

Ed. note:  The following table has 6 columns.

                           dead/   dead within   diarrhea   off feed
drug      dose(mg/kg bw)   alive      % days      (days)     (days)

Placebo 0 0/6 --- 0 0-4 Bovatec 1 0/6 --- 0 0-3 Bovatec 10 0/6 --- 0-3 1-2 Bovatec 50 5/6 2-22 0-10 2-9 Bovatec 100 5/6 1 1-12 1-7

6. Human Safety

Numerous tests have been conducted to assess and assure human safety. They include long-term 2-1/2 year chronic rat studies, 2 year chronic mouse studies, 2 year chronic dog studies, reproduction studies and mutagenicity testing. The similarity of metabolism in the target animal (cattle) and the species used in the chronic studies has also been established by radiolabeled studies. In order to assess and quantify the potential tissue residues, studies with 14C-labeled drug have been conducted with appropriately sized cattle.

The studies in the bile cannulated rat indicate the bioavailability of lasalocid-derived tissue residues to be about one-half that of pure lasalocid added in the feed, suggesting a decreased potential for human exposure to lasalocid-derived tissue residues.

The results of these studies performed to date indicate that residues of lasalocid are not carcinogenic, not teratogenic, not significantly cardioactive, not toxic following long or short-term ingestion, and are not a reproductive hazard. Furthermore, because including target and test animals, were qualitatively and quantitatively similar, the test animals (which act as surrogates for the human population) were properly exposed to target animal lasalocid residues through autoexposure.

A suitable fluorescent hplc determinative procedure and a gas chromatographic mass spectrometry-confirmatory procedure have been developed. These methods have been successfully validated in the FSIS/USDA and FDA/HHS laboratories. The determinative and confirmatory assays for residues are filed in the Food Additives Analytical Manual on display in the Public Records and Document center, Room 4-62, 5600 Fishers Lane, Rockville, Maryland 20857.

Specific information of the tests and rusults in safety studies are as follows.

Long-Term Chronic Studies

2-Year Chronic Dog Study. Eighty 4-1/2 month old beagle dogs were used in the test which evaluated lasalocid doses of 0, 10, 35 and 180 ppm of lasalocid addition to their diet; 10 animals were used per group, which included a male and female group on each treatment. The only significant toxicological effect produced was the highest dosed group, 180 ppm, which showed an increase on serum alkaline phosphatase and a decrease in prostatic weight. The "no-observed-effect level" was 35 ppm, which equated to 1 mg/kg/day intake.

2-1/2 Year Chronic Rat Study. A total of 680 rats were used in the bioassay which included feeding lasalocid at a level of 0, 10, 35 and 120 ppm; 85 rats were used per group with a male and female group being evaluated at each dose level. A second control group was used employing 55 rats of each sex. This bioassay demonstrated that lasalocid was not carcinogenic and the "no-observed-effect level" was 120 ppm.

2-Year Chronic Mouse Study. The 2-year mouse study was conducted at feeding levels of 0, 10, 30 and 120 ppm of lasalocid in the diet. It employed two control groups; 80 mice were used per sex per group resulting in the employment of of 800 animals for this study. The 2-year bioassay in mice indicated lasalocid was not a carcinogen and indicated a "no-observed-effect level" of 120 ppm.

Multi-Generation Reproduction Test. This 3-generation study begining with 35 per sex per group included the evaluation of lasalocid addition of 0, 10, 35 and 120 ppm. This test, involving mice, showed that lasalocid addition gave no teratogenic response and the "no-observed-effect level" of 120 ppm, equating to an indication of 2.4 mg/kg/day.

Mutagenicity Tests

Lasalocid and its metabolites did not produce significant levels of revertants in the Ames salmonella reversion tests and, therefore, no mutagenic response was noted in this test.

Tissue Residue Evaluations

Studies with 14C-lasalocid were conducted in six cattle fed with lasalocid at 0.5, 1 and 2.0 mg/kg/day for a 14 day period (equivalent to 22.5, 45 and 90 g/ton, respectively). The highest dose proposed for approved use is 30 g/ton in cattle feed. Cattle representative of the animals that would be receiving lasalocid under use conditions were employed. Radiotracer studies indicated that an equilibrium in blood had been established after 5 to 7 days of drug administration. The liver was established as the target organ.

Evidence was provided using an electrically driven guinea pig atria model, which indicates that residues in the liver of lasalocid treated steers are no more cardioactive than residues from untreated steer liver and that fecal extracts from lasalocid treated steers are less cardioactive than fecal extracts from untreated steers. A qualitative similarity of metabolism was shown for the target animal (cattle) and the species used in the longterm chronic studies (dog, rat and mouse) as well as the chicken. The metabolic profiles from steers, dogs and rats were quantitatively similar, as were those from mice and chickens.

These data support the establishment of the allowable liver tolerance of 4.8 ppm for total residues with an Rm of 0.7 for the marker residue, intact lasalocid. The feeding of a ration containing 30 g of lasalocid per ton to steers does not give a liver residue that exceeds these tolerance levels when the animals are slaughtered with no withdrawal period.

The surveillance of potential tissue residue is possible by the FDA/HHS approved assay procedures. Adequate methodology for the determination and confirmation of lasalocid in bovine liver at Rm (0.7 ppm) and above has been developed and validated in three government laboratories (2-FDA/HHS; 1-FSIS/USDA). The regulatory method has a sensitivity of 25 to 50 parts per billion (ppb).

7. Agency Conclusions

The agency finds that the safety assessments using the test animal models, along with target animal studies, are valid and in conformity with current Agency concepts, practices and evaluation criteria. Data provided by the sponsor indicated no concern for carcinogenic potential for lasalocid, thus exempting the sponsor from the complete data collection provisions of the "Sensitivity of Methods" proposal (44 FR 17070, March 20, 1979). Other data provided by the sponsor were also adequate to satisfy that appropriate regulatory methodology had been developed.

The sponsor has presented adequate and appropriate human safety data for approval of lasalocid use in beef cattle under the safety provisions of section 512(d) of the Federal Food, Drug and Cosmetic Act. Accordingly, lasalocid use in beef cattle at 10 to 30 g/ton feed with a zero day withdrawal period has been shown to be safe.

Adequate and well-controlled investigations discussed above demonstrate the safety and effectiveness of lasalocid when used under the proposed conditions of use for improved feed efficiency and increased rate of weight gain in beef cattle fed in confinement for slaughter.

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