NADA 097-505

A. Toxicity Tests and Tolerance

Toxicity tests are addressed in the FOI Summary included with a Supplemental New Animal Drug Application (NADA 111-636). The FOI Summary was made available 31 January 1990 (55 FR 3208/9).

No tolerance is required for the 20 and 40 g/ton use levels of lincomycin in swine. The previously established tolerance of 0.1 part per million for negligible residues of lincomycin in the edible tissues of swine (21CFR 556.360) still applies to the 100 and 200 g/ton use levels of lincomycin in swine and is not affected by this supplement.

B. Safe Concentration of Total Residues

1. No Observed Effect Level
As referenced in the FOI Summary for NADA 111-636, the lowest No Observed Effect Level (NOEL) from the oral feeding toxicity studies is 30 mg/kg body weight.

2. Safe Concentration (SC) Calculations
Safe Concentration = (ADI x Weight of Average Adult)
                     _______________________________
                     
                      Daily Consumption of Meat
Where:
Acceptable Daily Intake (ADI) = (lowest NOEL)/(Safety Factor)
and Safety Factor (SF) of 1000 is used because 90 day feeding study data were used.
Daily Consumption of Meat is 500 grams.
Weight of an average adult is 60kg.
Lowest NOEL (No Observable Effect Limit) is 30mg/Kg,
Therefore:

ADI = 0.03/kg and
SC  =  (0.03mg/kg x 60kg)/500g  =  3.6 g/kg or 3.6ppm
Present FDA policy limits SC to no more than 3.0 ppm unless chronic toxicity data were used for the SC calculations.

Using the Consumption Factors cited in the CVM Guideline, Guideline for Establishing a Tolerance, dated September 1986, the following SC values apply per swine tissue:
Tissue        Factor      S.C.(ppm)

Muscle          1           3.0
Kidney         1/4         12.0
Liver          1/3          9.0
Fat            1/4         12.0
C. Total Residue Depletion and Metabolism Studies

1. Investigator:
R.E. Hornish
The Upjohn Company
Kalamazoo, MI 49001
C. Total Residue Depletion and Metabolism Studies Continued

2. Animals used: Six pigs per treatment group, three male and three female. Animals weighed 30-50 kg and were 10-16 weeks of age at time of initial treatment

3. Route of drug administration: ¹⁴C lincomycin (Carbon 14 Lincomycin, C-14 Lincomycin) was administered ad libitum via feed.

4. Time and duration of dosing: Non-medicated feed was provided 4-7 days prior to treatment followed by ¹⁴C labeled lincomycin in the feed for 72 hours. Fresh feed was provided at 24 hour intervals. Non-medicated feed was provided for 12 hours post-drug exposure then animals were sacrificed for residue determination.

5. Radioisotope used in this study: ¹⁴C labeled lincomycin hydrochloride.

6. Average Total Residue Concentrations

Total C-14 Residue Concentrations* (ppm) of Lincomycin at Zero Day Withdrawal (approximately 12 hours post last treatment)
Use Level       
(g/ton  
complete          ----------------------Tissue----------------------
feed)             Liver          Kidney         Muscle           Fat 

 20   mean**       0.40           0.22           0.01           0.02          
       SD***       0.08           0.03           0.003          0.01          
 40   mean         0.64           0.41           0.02           0.02          
       SD          0.27           0.19           0.004          0.01          
100   mean         1.64           1.25           0.05           0.13          
       SD          0.83           0.48           0.02           0.11          
^**Mean of 6 animals.
^*** Standard deviation from sample of 6.
* Concentrations expressed as lincomycin free base equivalents. In addition, microbiological assays on edible tissues of the swine from the 20 and 40 g/ton groups show parent lincomycin to be less than 0.1 ppm at zero day withdrawal, the tolerance that still applies for the 100 and 200 g/ton use levels.
7. Comparative Metabolism
High Pressure Liquid Chromatographic and Thin Layer Chromatographic procedures were used to profile metabolites of lincomycin in the urine, feces and liver of swine and rats each orally administered ¹⁴C labeled lincomycin hydrochloride.

Rats were dosed at 15 or 300 mg/kg body weight whereas swine were dosed at 200 g/ton of complete feed. Rats were sacrificed while on treatment. Two pigs were sacrificed four hours post last treatment and two at six days post treatment. Non-medicated feed was administered to pigs during the six day preslaughter drug withdrawal interval.

Feces and gastrointestinal tract contents of pigs and rats contained the major portion (70%) of the excreted drug. Excretion in both species is mostly by the GI tract due, in part, to the poor oral absorption of lincomycin.

The most prevalent compound in urine of rats and swine is parent lincomycin. In addition to lincomycin there are 15 other metabolites in swine urine of which 10 are also present in urine of rats.

Parent lincomycin is the most prevalent compound in the feces of rats and swine, excepting in swine at two days (48h) post last treatment when lincomycin concentrations in feces is extremely low. Of the six other metabolites present in feces of swine tested while on treatment, three are also present in feces of rats.

Metabolites of lincomycin are extensive in the liver, numbering 26, which includes parent lincomycin. Of these, 20 are also present in liver of orally treated rats. These 20 metabolites comprise at least 90% of the total residue and, therefore, additional studies were not required for assessing the toxicological concern of the remaining metabolites.

Collectively, the urine, feces and liver profiles show quantitative differences between rat and swine in the metabolism of lincomycin but a remarkable similarity on a qualitative basis. Nearly all metabolites found in the swine urine, feces and liver were also present in corresponding samples from rats. Therefore, rats used in the toxicity study were auto-exposed to the same compounds as would humans consuming uncooked edible tissues of lincomycin treated swine.

D. Establish the Withdrawal Period

Total ¹⁴C lincomycin residue data for several feed use levels demonstrate that total residues are well below the established safe concentrations per tissue at zero day withdrawal, even when administered at exaggerated doses (i.e., at 100 g/t which is 2.5x the 40 g/t use level), thereby supporting the zero day withdrawal for the 20 and 40 g/t feed use levels.

Total C-14 Residue Concentrations (ppm) at Zero Day Withdrawal for 20 and 40 g/ton Feed Use Levels

(Eds. note: the following table contains 6 columns)
            Calculated      
            Safe        
            Consumption  Concentration  ----------Mean ± Standard Deviation----------
Tissue      Factor           (ppm)          20 g/t         40 g/t         100 g/t

Muscle        1x               3        0.011 ± 0.003    0.019 ± 0.004     0.05 ± .02    
Kidney        1/4x            12        0.218 ± 0.029    0.405 ± 0.185     1.25 ± .48    
Liver         1/3x             9        0.40 ± 0.081     0.644 ± 0.265     1.64 ± .83    
Fat           1/4x            12        0.021 ± 0.012    0.024 ± 0.012     0.13 ± .11    

N=6 for all tissues per drug use level.
E. Regulatory Method
No regulatory method is required for the 20 and 40 g/ton use levels of lincomycin in swine.

F. Anti-microbial Drugs Intended for Long-term, Subtherapeutic Use in Animal Feeds

Please refer to the FOI Summary made Available 30 June 1976 (41 FR 26855), for referral to studies completed in accordance with provisions of 21CFR558.15.

VII. AGENCY CONCLUSIONS:

The data submitted in support of this NADA satisfy the requirements of Section 512 of the Act and demonstrate that human food products derived from swine when fed lincomycin at 20 g/ton and at 40 g/ton with a zero withdrawal period are safe.

This supplemental NADA is regarded as a Category II application under CVM's supplemental policy, (42 FR 64367; December 23, 1977), and which required a complete review of the food safety data. The supplement provides for establishment of a safe concentration and a shortening of the withdrawal period from 6-days to 0-days for swine fed lincomycin at 20 and 40 grams per ton of complete feed. The sponsor has provided all the toxicological (by reference to NADA 111-636) and residue chemistry data that are necessary for the approval of the supplemental application.

Data from a two generation toxicology study show a no observed effect level (NOEL) of 1000 mg/kg. The safe concentration for lincomycin was calculated (1000x safety factor) on the basis of the 30 mg/kg NOEL for embryotoxicity. The safe concentration calculated for total residues at zero days of drug withdrawal are: 3 ppm for muscle, 9 ppm for liver, 12 ppm for kidney and fat. Comprehensive metabolism studies established that rats are exposed essentially to the same metabolites as are humans consuming edible products from swine treated with lincomycin; therefore, further toxicity testing was not required. Residue depletion studies in this application demonstrate that total residues of lincomycin (from 14-C labeled lincomycin studies) are well below the calculated safe concentrations when the drug is fed to swine at 20 and 40 grams per ton of feed. In addition, residues of parent lincomycin in edible tissues of swine treated with 20 and 40 g/ton were less than 0.1 ppm, the tolerance that still applies for the 100 and 200 g/ton use levels.

The shortening of the withdrawal period from 6-days to 0-day, for swine fed lincomycin at 20 and 40 grams per ton, qualifies lincomycin to be classified as a Category I drug, under 21CFR558.4. This change to Category I also, changes the upper limit for drug concentration of the Type B medicated feeds from 10 grams to 20 grams per pound of product.

NADA	097-505
Sponsor:	The Upjohn Company 7000 Portage Road Kalamazoo, Michigan 49001
Generic Name:	lincomycin hydrochloride
Trade Name:	Lincomycin Premixes
Marketing Status:	Over the Counter (OTC)
Effect of Supplement:	This supplement provides for the following actions concerning use of Lincomycin in swine feed at the 40 and 20-gram-per-ton levels: (1) removal of the 6-day, preslaughter, drug withdrawal requirement; and (2) removal of the Lincomycin entry from the Category II table and addition of same to the Category I table in 21CFR 558.4.

A.	DOSAGE FORM	Medicated premix (Type A Medicated Article) and is available in two concentrations: 20 and 50 grams lincomycin per pound.
B.	ROUTE OF ADMINISTRATION	Oral via feed
C.	RECOMMENDED DOSAGES:	For increase in rate of weight gain in growing-finishing swine, feed 20 grams of lincomycin per ton of complete swine feed. For control of swine dysentery, feed 40 grams of lincomycin per ton of complete swine feed.