United States Oftio) of Posticidas and Toxic Substances
Environmental Protection Office of Pesticide Programs (TS-766CI
Agency Washington, DC 20460
540/FS-89-017
oEPA Pesticide
Fact Sheet
Name of Chemical: OXYTETRACYCLINE
Reason for Issuance: REGISTRATION STANDARD
Date Issued: DECEMBER 1988
Facf Sheet Number:
1. DESCRIPTION OF CHEMICAL
Generic Name: Qxytetracycline
Qxytetracycline calcium complex
Qxytetracycline hydrochloride
Chanical Name: 4-(dimethylamino)-l,4,4a,5,5a,6,ll,12a-octahydro-
3 , 5 , 6 , 10 , 12 , 12a-hexahydro-6-methyl-l , ll-dioxo-2-
naphthacenecarboxamide and its calcium conplex and
hydrochloride salts.
Trade Names: Glomycin, Terraf ungine , Riomitsin, Hydroxy-
tetracycline, Bertanycin, Biostat, Impercin, Qxacycline, Qxyatets,
Mycoshie.ld, Agricultural Terramycin, Terramycin Hydrcxiiloride ,
Terramycin.
Chemical Class: Antibiotic (produced by the actinonycete
Streptomyces rimosus)
Pesticide Type: Plant Fungicide/Bactericide and Algicide
CAS Registry Number: 79-57-2 (oxytetracycline)
7179-50-2 (calcium conplex)
2058-46-0 (hydrochloride)
EPA Shaughnessy Codes: 006304 (oxytetracycline)
006321 -(calcium complex)
006308 (hydrochloride)
Brpirical Formulae: C22^2^N2°S (oxytetracycline) Mol. Wt. 460.44
C22H22N2°9 ^ (calcium complex) M.W. 498.52
-C22H24N2°9 .HCL (.hydrochloride) M.W. 496. 9
Year of Initial Registration: August 1974
U.S. and Foreiqn Producers: Pfizer, Inc.
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2. USE FKT1TOMS »Nn FORMfflJOTICNS
Type of Pesticide: Plant Fungicide/Bactericide and Algicide.
Pests Controlled: Bacterial and fungal diseases and slime-forming
microorganisms.
Registered Uses:
1. Calcium oxytetracycline [17% WP]:
Nectarines, peaches, pears, and creeping
Bentgrasses.
2. Oxytetracycline hydrochloride [21.6%
Soluble Concentrate.
-(Tree Trunk Injection) pears, peaches, and
ornamental palms)
- Marine antifoulant paint additive.
3. Qxytetracycline hydrochloride [21.6%
Soluble Concentrate.
Formulation Intermediate for Marine
antifoulant additive.
Predominant Uses: Pears and peaches (98%).
Minor Uses: Ornamental palms and Bentgrasses.
Annual Usage: 21,350 pounds/ai
Method of Application: Foliar, tree injection, and
brush on (marine use).
3. SCTEMCE FINDINGS
Summary Science Statement
1. Qxytetracycline hydrochloride oncogenicity data indicates equivocal
evidence of oncogenicity in male and female rats. The Agency concludes that,
although the findings were termed "equivocal" by the National Toxicology Program,
they do not represent positive evidence of carcinogenicity in the rat. A
similar study in mice indicated no evidence of oncogenicity.
2. Tolerances for oxytetracycline are limited to peaches (which includes
nectarines) and pears, 0.1 ppm and 0.35 ppm respectively. A Reference Dose (RfD)
of l.O mgAg/day has been established based on several chronic studies. The
Theoretical Maximum Residue Contribution (TMRC) for the U.S. population is
0.000065 mgAg/day/ corresponding to 0.006% of the RfD. A proposed increase in
the peach tolerance from 0.1 to 0.35 ppm would result in a TMRC of 0.000118
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mg/kg/day. The largest subgroups, nursing and non-nursing infants, represent
0.061% and 0.076% respectively of the current RfD.
3. The potential for development of oxytetracycline resistance due to
increased background levels from pesticidal uses to applicators and field workers
appears minimal.
4. The Agency is unable to assess the potential for oxytetracycline to
contaminate ground water because the environmental fate of oxytetracycline is
uncharacterized.
5. The Agency is unable to assess the ecological effects of oxytetracycline
on terrestrial or aquatic wildlife, because no data are available.
Toxicology Characteristics
Qxytetracycline has been used extensively for over 37 years in animals
and in man. It is one of a group of broad spectrum antibiotics known as
tetracyclines which were developed for control of bacterial diseases in man and
animals. As a result of its human drug use, there is an extensive body of
toxicological data available on oxytetracycline. Thus, all toxicological data
requirements have been waived.
Chronic toxicity
Due to various deficiencies, the available studies do not fulfill current
requirements. Additional data are not required, based upon availability of both
animal and human data from oxytetracycline's drug uses.
Two 2-year chronic toxicity studies in rats are available. In one study,
Osborne-Mendel rats were fed diets containing 0, 100, 1000 and 3000 ppm,
oxytetracycline hydrochloride in. the diet for 24 months. The NOEL was determined
to be 3000 ppm, approximately 150 mg/kg/body weight/day, highest dose tested.
In a second study, Sprague Dawley rats were fed diets containing 0,100, and
1000 ppm oxytetracycline hydrochloride in the diet for 24 months. The NOEL for
oxytetracycline hydrochloride was 1000 ppm, 50 mg/kg/day, highest dose tested.
Two chronic toxicity studies in dogs are available. In the first study,
dogs were fed diets containing 0, 100, 3000, and 10000 ppm of oxytetracycline
hydrochloride in the diet for 24 months. A yellow discoloration of the long
bones and brownish discoloration of the thyroid was observed in all dosed animals
at necropsy. The NOEL was determined to be 10000 ppm, approximately 250
mg/kg/day, highest dose tested.
In a second study, mongrel dogs were fed diets containing 0, 5000, and
10000 of oxytetracycline hydrochloride in the diet for 12 months. The NOEL was
determined to be 10000 ppm, approximately 250 mg/kg/day, highest dose tested.
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Oncogenicitv
NCI/NTP Qxytetracycline Qncogenicity Study in the F344N/Rat
In this study, oxytetracycline hydrochloride (purity 98.8%) was administered
to groups of F344/N rats fed 0, 25000, and 50000 ppm in the diet for 103 weeks.
Fatty metamorphosis of the liver was increased in rats in the low dose group.
Die National Toxicology Program concluded that ". . . . there was equivocal
evidence1 of carcinogenicity for male F344/TJ rats as indicated by increased
incidences of pheochromocytomas of the adrenal gland. There was equivocal
evidence of carcinogenicity for female F344/N rats as indicated by increased
incidences of adenomas of the pituitary gland in the high dose group."
NCI/NTP Qxytetracycline Qncogenicity Study in the B6C3F1 lYbuse
In this study, oxytetracycline hydrochloride (purity 98.8%) was administered
to groups of B6C3F1 mice fed 0, 6300, and 12500 ppm in the diet for 103 weeks.
The National Toxicology Program concluded that "... there was no evidence of
carcinogenicity for male or female B6C3F1 mice fed diets containing 6300 or 12500
ppm of oxytetracycline hydrochloride for. 2 years."
Teratogenic itv
Female Charles River CD rats were dosed during days 6 through 15 of
gestation with 1200, 1350, or 1500 rog/kg of oxytetracycline hydrochloride.
There were dose-related decreases in maternal survival and body weight gain, and
increases in the incidence of respiratory difficulties and rough coat. In
addition, there were significant dose-related decreases in the percent of treated
dams found pregnant. There was also a dose-related decrease in fetal body weight.
The high incidence of maternal deaths and the fetotoxicity noted in all dose
levels tested did not allow for an establishment of a NOEL. The T.FT. was 1200
mg/kg/day (lowest dose tested).
The significant findings discussed in this study can be attributed to the
excessive dose levels used, and the overly stressing of the treated dams.
Female CD-I mice were dosed during day 6 through 15 of gestation with 0,
1325, 1670, and 2100 mg/kg oxytetracycline hydrochloride. No adverse effects
were demonstrated, due probably to the low dose levels used. The NOEL for
maternal and developmental toxicity in this study was 2100 mg/kg (highest dose
tested).
1 The NCI/TSTTP uses five levels of interpretative evaluations in animal
carcinogenesis studies; in decreasing order of strength (not potency or
mechanism) of the experimental evidence, these are: (i) clear evidence
ofcarcinogenicity (ii) some evidence of carcinogenicity, (iii) equivocal evidence
of carcinogenicity, (iv) no evidence of carcinogenicity, and (v) inadequate study
of carcinogenicity.
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Antibiotic Microbial Resistance
Mature beagles were fed a diet containing 0, 2, or 10 ppm, approximately of
oxytetracycline for 44 days. The 10 ppm (0.25 mg/kg/day) diet resulted in a
shift from a predominantly drug-susceptible population of enteric lactose-
fermenting organisms to a multiple antibiotic-resistant population. A shift to
drug-resistance did not occur in the group fed 2 ppm approximately 0.05
mg/kg/day. The NOEL was 0.05 mg/kg/day.
4. TOLESffiKCE ASSESSMENT
Tolerances have been established for residues of oxytetracycline in two raw
agricultural commodities (40 CFR 180.337). Use of oxytetracycline as a drug in
food animals is regulated by the FUV according to 21 CFR 520, 522, 524, and 558.
The Fm has established tolerances for oxytetracycline in or on meat, fat, meat
byproducts, and in uncooked edible tissues of salmonoid fish and catfish (21 CFR
556.500).
No data are available to evaluate the nature of the residue of
oxytetracycline in plants. The Agency has assessed the need for data reflecting
the metabolism of oxytetracycline in plants and has concluded that these data
are not required because of the drug uses of oxytetracycline.
No data are available to evaluate the nature of the residue of
oxytetracycline in animals. However, data on the metabolism of oxytetracycline
in food animals are not required: residues of oxytetracycline in meat and milk
are unlikely since there are no registered uses of animal feed items at the
present time.
The available microbiological assay method for the determination of
oxytetracycline residues in or on peaches, nectarines and pears is adequate for
data collection and for tolerance enforcement. The Agency will not require any
additional analytical methods at this time. The method is similar to Final
Action Microbiological Methods I and II in the AOAC Official Methods of Analysis
(1984;42.293-42.298).
5. summary of Regulatory Positions
Oxytetracycline is not a candidate for Special Review at this time.
Oxytetracycline does not meet the criteria for restricted use
classification.
The Agency will continue to grant new uses for oxytetracycline.
The Agency will propose that the tolerance level for peaches be increased
from 0.1 ppm to 0.35 ppm.
The Agency will not propose the establishment of crop group tolerances
for pome fruits or stone fruits.
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Current tolerances are sufficient to cover the actual residues resulting
from tree injections (pears only) and foliar applications.
The Agency is deferring its decision.concerning the potential of
oxytetracycline to contaminate groundwater until information on its
environmental fate has been sutmitted and evaluated.
The Agency believes that the potential for development of resistant
microorganisms in applicators and/or field workers as a result of
exposure are negligible.
Potential for development of oxytetracycline resistant microorganisms
as a result of dietary exposure is minimal.
6. Summary of Mferjor Data Gaps
Environmental fate/Exposure:^
Hydrolysis
Photodegradation in water and in soil
Metabolism Studies (lab)
-Aerobic Soil
-Anaerobic Soil
-Anaerobic Aquatic
-Aerobic Aquatic
Leaching and Adsorption/Desorption
Dissipation Studies (field)
-Soil
-Aquatic (Sediment)
Accumulation in Fish
Timeframe for
Submission
9
9
Months
Months
27 Months
27 Months
27 Months
27 Months
12 Months
27 Months
27 Months
12 Months
Fish & Wildlife;
Avian Acute Oral LD50
Avian Dietary LC50
Freshwater Fish LC50 (TSM)3
Freshwater Invertebrate (TStf)
Product Chemistry
All product chemistry studies
9
9
9
9
Months
Months
Months
Months
Months
Environmental Fate data requirements only for calcium
oxytetracycline.
TGAI: Technical grade of the active ingredient
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7. OCUBVCT PERSON AT
Larry Schnaubelt
Product Manager (21)
Herbicide/Fungicide Branch
Registration Division (TS-767C)
Office of Pesticide Programs
Environmental Protection Agency
401 M Street, S. W.
Washington, D. C. 20460
Office location and telephone number:
Room 227, Crystal Mall #2
1921 Jefferson Davis Highway
Arlington, VA 22202
(703) 557-1900
DISCXAIMR: The information in this Pesticide Fact Sheet is a
summary only and is not to be used to satisfy data requirements for
pesticide registration and reregistration. The complete Registration
Standard for the pesticide may be obtained from the National Technical
Information Service. Contact the Product Manager listed above for
further information.
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