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NATIONAL TOXICOLOGY PROGRAM Technical Report Series No. 338

TOXICOLOGY AND CARCINOGENESIS

STUDIES OF

ERYTHROMYCIN STEARATE

(CAS NO. 643-22-1)

IN F344/N RATS AND B6C3F1 MICE

(FEED STUDIES)

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

National Institutes of Health

I '

NTP TECHNICAL REPORT

ON THE

TOXICOLOGY AND CARCINOGENESIS

STUDIES OF ERYTHROMYCIN STEARATE

(CAS NO. 643-22-1)

IN F344/N RATS AND B6C3F1 MICE

(FEED STUDIES)

John Edgar French, Ph.D., Chemical Manager

NATIONAL TOXICOLOGY PROGRAM

P.O. Box 12233

Research Triangle Park, NC 27709

December 1988

NTP TR 338

NIH Publication No. 89-2594

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Institutes of Health

NOTE TO THE READER

This study was performed under the direction of the National Institute of Environmental Health Sci- ences as a function of the National Toxicology Program. The studies described in this Technical Re- port have been conducted in compliance with NTP chemical health and safety requirements and must meet or exceed all applicable Federal, state, and local health and safety regulations. Animal care and use were in accordance with the U.S. Public Health Service Policy on Humane Care and Use of Ani- mals. All NTP toxicology and carcinogenesis studies are subjected to a data audit before being pre- sented for public peer review.

Although every effort is made to prepare the Technical Reports as accurately as possible, mistakes may occur. Readers are requested to identify any mistakes so that corrective action may be taken. Further, anyone who is aware of related ongoing or published studies not mentioned in this report is encouraged to make this information known to the NTP. Comments and questions about the National Toxicology Program Technical Reports on Toxicology and Carcinogenesis Studies should be directed to Dr. J .E . Huff, National Toxicology Program, P.O. Box 12233, Research Triangle Park, NC 27709 (919-541-3780).

These NTP Technical Reports are available for sale from the National Technical Information Service, U.S. Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161 (703-487-4650). Single copies of this Technical Report are available without charge (and while supplies last) from the NTP Public Information Ofice, National Toxicology Program, P.O. Box 12233, Research Triangle Park, NC 27709.

Ery thromycin Stearate, S T P TR 338 2

CONTENTS PAGE

ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

EXPLANATION O F LEVELS O F EVIDENCE OF CARCINOGENIC ACTIVITY . . . . . . . . . . . . . . . . . . 8

CONTRIBUTORS ............................................................ 9

P E E R R E V I E W P A N E L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

SUMMARY O F P E E R REVIEW COMMENTS ......................................... 11

I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

II. MATERIALS AND METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

PROCUREMENT AND CHARACTERIZATION OF ERYTHROMYCIN STEARATE . . . . . . . 20

PREPARATION AND CHARACTERIZATION O F FORMULATED DIETS . . . . . . . . . . . . . . 20

FOURTEEN-DAYSTUDIES ............................................. 25

THIRTEEN-WEEK STUDIES ............................................. 25

TWO-YEARSTUDIES ................................................. 25

STUDYDESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

SOURCE AND SPECIFICATIONS O F ANIMALS ............................ 27

ANIMAL .MAINTENANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

CLINICAL EXAMINATIONS AND PATHOLOGY ............................ 28

STATISTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

III. RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

RATS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

FOURTEEN-DAYSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

THIRTEEN-WEEK STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

TWO-YEAR STUDIES .............................................. 33

BODY WEIGHTS. F E E D CONSUMPTION. AND CLINICAL SIGNS . . . . . . . . . . . . 33

SURVIVAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

PATHOLOGY AND STATISTICAL ANALYSES OF RESULTS . . . . . . . . . . . . . . . . 36

MICE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

FOURTEEN-DAYSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

THIRTEES-WEEKSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

TWO-YEAR STCDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

BODY WEIGHTS. FEED CONSUMPTION. AND CLINICAL SIGNS . . . . . . . . . . . . 4 1

SURVIVAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

PATHOLOGY AND STATISTICAL ANALYSES O F RESC'LTS . . . . . . . . . . . . . . . . 44

IV . DISCUSSION AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

V . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

3 Erythromycin Stearate. NTP TR 338

APPENDIXES PAGE

APPENDIX A

APPENDIX B

APPENDIX C

APPENDIX D

APPENDIX E

APPENDIX F

APPENDIX G

APPENDIX H

APPENDIX I

SUMMARY O F LESIONS IN MALE RATS IN T H E TWO-YEAR FEED STUDY O F ERYTHROMYCIN STEARATE .......................... . . . . . . . . . . . 57 SUMMARY O F LESIONS IN FEMALE RATS IN T H E TWO-YEAR F E E D STUDY OF ERYTHROMYCIN STEARATE ..................................... 83 SUMMARY OF LESIONS IN MALE MICE IN THE TWO-YEAR FEED STUDY O F ERYTHROMYCIN STEARATE ..................................... 105 SUMMARY O F LESIONS IN FEMALE MICE IN THE TWO-YEAR FEED STUDY O F ERYTHROMYCIN STEARATE . . . . , . . . .. . . . . . . . , . . . . . . . . . . . . . . . . . . . 125 GENETIC TOXICOLOGY OF ERYTHROMYCIN STEARATE . . . . . . . . . . . . . . . . . . . 145 SENTINEL ANIMAL PROGRAM . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 FEED AND COMPOUND CONSUMPTION BY RATS AND MICE IN THE TWO-YEAR FEED STUDIES OF ERYTHROMYCIN STEARATE .. . . . . . . . . . . . . . . . . . . . . . . . 153 INGREDIENTS, NUTRIENT COMPOSITION, AND CONTAMINANT LEVELS IN NIH 07 RAT AND MOUSE RATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L59 AUDIT SUMMARY . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Erythromycin Stearate, S T P TK 338 4

H H CH3 CH3 .o I

C2H5 0

ERYTHROMYCIN STEARATE

CAS NO. 643-22-1

C37H67N013 ' C18H3602 Molecular weight 1,018

Synonyms: erythrocin stearate; erythromycin octadecanoate

Trade names: Abbotcine; Bristamycin; Dowmycin E; Eratrex; Erypar; Ethril; Gallimycin; HSDB 4178; OE 7; Pantomicina; Pfizer-E; SK-Erythromycin; Wyamycin S

ABSTRACT

Toxicology and carcinogenesis studies of erythromycin stearate (USP grade, greater than 96% pure) were conducted by administering the antibiotic in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Erythromycin stearate was studied because of its wide- spread use in humans a s a broad-spectrum macrolide antibiotic and because of the lack of adequate long-term studies for carcinogenicity.

Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, none of the rats (at dietary concen- trations up to 50,000 ppm) and 215 female mice that received 50,000 ppm died before the end of the studies. Final mean body weights of male rats that received 12,500,25,000, or 50,000 ppm were lo%, 30%, or 36% lower, respectively, than that of controls; final mean body weights of female rats were lo%, 12%, or 32% lower. None of the dosed mouse groups gained weight. The final mean body weight of male mice that received 50,000 ppm was 10% lower than that of controls.

In the 13-week studies, none of the rats or mice (at dietary concentrations up to 20,000 ppm) died be- fore the end of the studies. Final mean body weights of the 20,000-ppm groups of rats were more than 12% lower than that of the controls for males and 7% lower for females. Final mean body weights of mice that received 10,000 or 20,000 ppm were 15% or 19% lower than that of controls for males