Approval Date: September 23, 1997

Freedom of Information Summary
NADA 048-761

I. GENERAL INFORMATION:

NADA	048-761
Sponsor:	Hoffmann La-Roche Inc. 340 Kingsland Street Nutley, New Jersey 07110
Generic Name:	chlortetracycline
Trade Name:	Aureomycin®
Marketing Status:	Over the Counter (OTC)
Effect of Supplement:	Changes all withdrawal times to zero (0) days when fed at certain doses.

II. INDICATIONS FOR USE

See below

III. DOSAGE:

A.	DOSAGE FORM	Type A Medicated Article
B.	ROUTE OF ADMINISTRATION	Oral
C.	RECOMMENDED DOSAGES:	Dose Class Indication Current Withdrawal Period Withdrawal Period, after this action 0.1 mg/lb of body weight/day Calves (up to 250 lbs) For an increased rate of weight gain and improved feed efficiency 0a 0 25-70 mg/head/day Calves (250-400 lbs) For an increased rate of weight gain and improved feed efficiency 0a 0 70 mg/head/day Growing Cattle (over 400 lbs) For an increased rate of weight gain, improved feed efficiency and reduction of liver condemnation due to liver abscesses 0a 0 350 mg/head/day Cattle For the control of bacterial pneumonia associated with shipping fever complex susceptible to chlortetracycline 48 hours 0 350 mg/head/day Beef cattle (under 700 lbs) Control of active infection of anaplasmosis caused by Anaplasma marginale susceptible to chlortetracycline 48 hours 0 0.5 mg/lb of body weight/day Beef cattle (over 700 lbs) Control of active infection of anaplasmosis caused by Anaplasma marginale susceptible to chlortetracycline 48 hours 0 10 mg/lb/day Calves, beef and nonlactating dairy cattle Treatment of bacterial enteritis caused by Escherichia coli and bacterial pneumonia caused by Pasteurella multocida organisms susceptible to chlortetracycline. Treatment for not more than 5 days. 10 days 0 0.5 - 2.0 mg/lb body weight/day Beef cattle, and non-lactating dairy cattle Control of active infection of anaplasmosis caused by Anaplasma marginale susceptible to chlortetracycline; when adminstered in a free-choice feed. 4 days 0 a Published in 61 FR 35949, July 9, 1996.
	NOTES

IV. EFFECTIVENESS:

No further effectiveness data are required.

V. ANIMAL SAFETY:

No further animal safety data are required

VI. HUMAN SAFETY:

A. TOLERANCE

Safety of the approved product, chlortetracycline premix, has been established by data in the original application, NADA 48-761.

Tolerances for chlortetracycline in edible tissue of beef cattle and nonlactating dairy cattle are 2 ppm in uncooked muscle, 6 ppm in uncooked liver, and 12 ppm in uncooked fat and kidney (21 CFR 556.150 per Federal Register, vol. 61, No. 247, p 67453).

B. STUDIES ESTABLISHING WITHDRAWAL PERIOD

i. Experiment: B-80-15, 10 mg per pound of body weight

P. E. Ginger of Princeton, New Jersey, directed the residue depletion study. Seventeen Angus Hereford calves (9 steers and 8 heifers) with an average weight of 439 lb were used in this study. Fourteen calves were treated orally with Aureomycin® chlortetracycline as crumbles top-dressed over a complete ration to provide 10 mg chlortetracycline per pound of body weight daily for 14 consecutive days. Two or three calves were sacrificed and samples of muscle, liver, kidney, and fat were collected at each of the following withdrawal points: 0, 5, 10, 14, and 21 days. Three calves were sacrificed as nonmedicated, control sources of the same tissues. All tissues from all control calves were negative (0.025 ppm or less) for chlortetracycline. Data for treated calves are summarized in Table 6Bi-1.

Table 6Bi-1. Concentration (ppm) of Chlortetracycline (CTC) in Edible Tissues of Cattle Following Indicated Withdrawal Periods after Treatment with 10 mg CTC per Pound of Body Weight.^†

Day Of Withdrawal	Muscle	Liver	Kidney	Fat
0	0.38 ± 0.05	1.93 ± 0.21	4.50 ± 0.79	0.05 ± 0.01
5	ND‡	0.05 ± 0.00	0.17 ± 0.01	ND
10	ND	ND	0.05 ± 0.02	ND
14	ND	ND	0.05 ± 0.02	ND
21	ND	ND	0.05 ± 0.01	ND
† Values are mean of detectable concentrations ± sample standard deviation. ‡ Indicates values were less than 0.025 ppm i.e., Non-Detectable

ii. Experiment: BB-64-4-FT, 5 mg per pound of body weight

H. Berger of Princeton, New Jersey, directed the residue depletion study. Twelve, two-year-old Holstein heifers with an average weight of 964 lb were used in this study. Nine heifers were treated orally with Aureomycin® chlortetracycline incorporated into a limit-fed, corn-protein supplement to provide 5 mg chlortetracycline per pound of body weight daily for 61 days. Three calves were sacrificed and samples of muscle, liver, kidney, and fat were collected at each of the following withdrawal points: 0, 3, and 10 days. Three calves were also sacrificed as nonmedicated, control sources of the same tissues at 1-day withdrawal. All tissues from all control calves were negative (less than 0.04 ppm) for chlortetracycline. Data for treated calves are summarized in Table 6Bii-1.

Table 6Bii-1. Concentration (ppm) of Chlortetracycline in Edible Tissues of Cattle Following Indicated Withdrawal Periods after Treatment with 5 mg Chlortetracycline per Pound of Body Weight.^†

Day Of Withdrawal	Muscle	Liver	Kidney	Fat
0	0.22 ± 0.03	0.99 ± 0.05	2.53 ± 0.84	0.02 ± 0.00
3	0.04 ± 0.01	0.18 ± 0.04	0.56 ± 0.14	ND‡
10	ND	ND	0.05 ± 0.02	ND
† Values are mean of detectable concentrations ± sample standard deviation. ‡ Indicates values were less than 0.04 ppm i.e., Non-Detectable

iii. Experiment: L-2469, 2 mg per pound of body weight

W. B. Epperson of Princeton, New Jersey, directed the residue depletion study. Twenty-seven Herefords (13 heifers and 14 steers) with an average weight of 598 lb were used in this study. Twenty-four head were treated orally with Aureomycin® chlortetracycline incorporated into a limit-fed grain, vitamin, and mineral supplement to provide 2 mg chlortetracycline per pound of body weight daily for 28 days. Four head were sacrificed and samples of muscle, liver, kidney, and fat were collected at each of the following withdrawal points: 24, 36, 48, 60, 72, and 84 hours. A single nonmedicated, control calf was also sacrificed at the 24, 48, and 72-hour withdrawal times. All tissues from all control cattle were negative (0.05 ppm or less) for chlortetracycline. Data for treated cattle are summarized in Table 6Biii-1.

Table 6Biii-1. Concentration (ppm) of Chlortetracycline in Edible Tissues of Cattle Following Indicated Withdrawal Periods after Treatment with 2 mg Chlortetracycline per Pound of Body Weight.^†

Hour Of Withdrawal	Muscle	Liver	Kidney	Fat
24	0.05	0.25 ± 0.05	0.45 ± 0.05	ND‡
36	ND	0.12 ± 0.03	0.25 ± 0.04	ND
48	ND	0.07 ± 0.01	0.15 ± 0.03	ND
60	ND	0.07 ± 0.00	0.11 ± 0.02	ND
72	ND	ND	0.06 ± 0.01	ND
84	ND	ND	0.06 ± 0.00	ND
† Values are mean of detectable concentrations ± sample standard deviation. ‡ Indicates values were less than 0.05 ppm i.e., Non-Detectable

iv. Experiment: B-77-4-FT, 280 or 460 mg per head

H. Berger of Princeton, New Jersey, directed the residue depletion study. Twenty-seven mixed breed steers with an average initial body weight of 690 lb were used in this study. Twenty-four steers were treated orally with Aureomycin® chlortetracycline as crumbles top-dressed on a portion of the complete ration to provide either 280 mg chlortetracycline (12 steers) or 460 mg chlortetracycline (12 steers) per head per day for 120 days. Three steers from each treatment were sacrificed and samples of muscle, liver, kidney, and fat were collected at each of the following withdrawal points: 0, 1, 2, and 3 days. Three nonmedicated, control steers were also sacrificed at the 0-day withdrawal time. All tissues from all control steers were negative (less than 0.025 ppm) for chlortetracycline. Data for treated calves are summarized in Table 6Biv-1 and Table 6Biv-2.

Table 6Biv-1. Concentration (ppm) of Chlortetracycline in Edible Tissues of Cattle Following Indicated Withdrawal Periods after Treatment with 280 mg Chlortetracycline.^†

Day Of Withdrawal	Muscle	Liver	Kidney	Fat
0	ND‡	0.08 ± 0.04	0.14 ± 0.07	ND
1	ND	0.06 ± 0.02	0.12 ± 0.05	ND
2	ND	0.04 ± 0.02	0.07 ± 0.02	ND
3	ND	ND	0.04 ± 0.01	ND
† Values are mean of detectable concentrations ± sample standard deviation. ‡ Indicates values were less than 0.025 ppm i.e., Non-Detectable

Table 6Biv-2. Concentration (ppm) of Chlortetracycline in Edible Tissues of Cattle Following Indicated Withdrawal Periods after Treatment with 460 mg Chlortetracycline.^†

Day Of Withdrawal	Muscle	Liver	Kidney	Fat
0	0.03 ± 0.00	0.18 ± 0.05	0.40 ± 0.08	ND‡
1	ND	0.08 ± 0.01	0.16 ± 0.04	ND
2	ND	0.07 ± 0.01	0.09 ± 0.01	ND
3	ND	0.04 ± 0.01	0.07 ± 0.03	ND
† Values are mean of detectable concentrations ± sample standard deviation. ‡ Indicates values were less than 0.025 ppm i.e., Non-Detectable

v. Experiment: B-85-63, 350 mg per head

M. N. Romano of Pennington, New Jersey, directed the residue depletion study. Twenty beef steers with an average body weight of 775 lb were used in this study. All twenty steers were treated orally with Aureomycin® chlortetracycline as a medicated, free-choice, 16% protein in ground corn supplement to provide approximately 350 mg per head per day for 14 days. Three steers were sacrificed and samples of muscle, liver, kidney, and fat were collected at each of the following withdrawal points: 1, 11/2, 2, 3, and 4 days. Data are summarized in Table 6Bv-1.

Table 6Bv-1. Concentration (ppm) of Chlortetracycline in Edible Tissues of Cattle Following Indicated Withdrawal Periods after Treatment with 350 mg Chlortetracycline.^†

Day Of Withdrawal	Muscle	Liver	Kidney	Fat
1	ND‡	0.05 ± 0.02	0.09 ± 0.03	ND
1 1/2	ND	0.03 ± 0.01	0.06 ± 0.01	ND
2	ND	0.03	0.04 ± 0.01	ND
3	ND	ND	ND	ND
4	ND	ND	ND	ND
† Values are mean of detectable concentrations ± sample standard deviation. ‡ Indicates values were less than 0.025 ppm i.e., Non-Detectable

Studies summarized in section 6B of this FOI have been statistically analyzed (95% confidence interval on the 99th percentile) per General Principles for Evaluating the Safety of Compounds used in Food-Producing Animals, Part VI, Guideline for Establishing a Withdrawal Period (revised July 1994). In each of the studies, the data support the assignment of a zero (0) withdrawal. Therefore, a zero (0) withdrawal is assigned for all of the approved dosage levels of chlortetracycline in cattle.

C. REGULATORY METHOD

The validated microbiological method (Antibiotic Residues in Milk, Dairy Products, and Animal Tissues: Methods, Reports, and Protocols, FDA, 1968) or a validated derivation thereof was used to measure antimicrobial activity of chlortetracycline in cattle tissues from each of the previously summarized studies. The limit of quantitation for specific methods used was 0.05 ppm or less. The validated microbiological method is on file at the Center for Veterinary Medicine, Food and Drug Administration, HFV-199, 5600 Fishers Lane, Rockville, Maryland 20855.

VII. AGENCY CONCLUSIONS:

This supplemental NADA satisfies the requirements of section 512(b) of the Federal Food, Drug and Cosmetic Act, and demonstrates that chlortetracycline (Aureomycin® - Type A medicated article) when used under the proposed conditions of use is safe and effective for the labeled indications.

Under the Center's supplemental approval policy (21 CFR 514.106(b)(2)(x)), this is a Category II change. The approval of this change required a reevaluation of certain safety data in the parent application with respect to the withdrawal period in beef cattle and non-lactating dairy cattle.

VIII. LABELING (Attached)

AUREOMYCIN 50, 90 and 100 - Type A medicated articles
Blue bird labeling for cattle feeds (Type C medicated feeds) for the following indications:
-For the treatment of bacterial enteritis caused by E. coli and bacterial pneumonia caused by P. multocida organisms susceptible to chlortetracycline in calves, beef and nonlactating dairy cattle.
-For the control of active infection of anaplasmosis caused by Anaplasma marginale susceptible to chlortetracycline in beef cattle under 700 pounds.
-For the control of active infection of anaplasmosis caused by Anaplasma marginale susceptible to chlortetracycline in beef cattle over 700 pounds.
-For the control of bacterial pneumonia associated with shipping fever complex caused by Pasteurella spp. susceptible to chlortetracycline in beef cattle.

Copies of applicable labels may be obtained by writing to the:

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857

Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.