oxytetracycline EPA Pesticide Fact Sheet 12/88
EPA Pesticide Fact Sheet
Name of Chemical: OXYTETYRACYCLINE
Reason for Issuance: REGISTRATION STANDARD
Date Issued: DECEMBER 1988
Fact Sheet Number: 188
1. DESCRIPTION OF CHEMICAL
- Generic Name: Oxytetracycline; Oxytetracycline calcium complex;
- Chemical Name: 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-
and its calcium complex and hydrochloride salts.
- Trade Names: Glomycin, Terrafungine, Riomitsin, Hydroxytetracycline,
Berkmycin, Biostat, Impercin, oxacycline, Oxyatets, Mycoshield,
Agricultural Terramycin, Terramycin Hydrochloride, Terramycin.
- Chemical Class: Antibiotic (produced by the actinomycete Streptomyces
- Pesticide Type: Plant Fungicide/Bactericide and Algicide
- CAS Registry Number: 79-57-2 (oxytetracycline)
7179-50-2 (calcium complex)
- EPA Shaughnessy Codes: 006304 (oxytetracycline)
006321 (calcium complex)
- Empirical Formulae: C22H24N209 (oxytetracycline) Mol.. Wt. 460.44
C22H22N2Og Ca (calcium complex) M.W. 498.52
C22H24N209 HCL (hydrochloride) M.W. 496.9
- Year of Initial Registration: August 1974
- U.S. and Foreign Producers: Pfizer, Inc.
2. USE PATTERNS AND FORMULATIONS
- Type of Pesticide: Plant Fungicide/Bactericide and Algicide.
- Pests Controlled: Bacterial and fungal diseases and slime-forming
- 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. Oxytetracycline 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 Founds/ai
- Method of Application: Foliar, tree injection, and brush on (marine
3. SCIENCE FINDINGS
Summary Science Statement
1. Oxytetracycline 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 1.0 mg/kg/day has been established based on several
chronic studies. The Theoretical Maximum Residue Contribution (TMRC)
for the U.S. population is 0.000065 mg/kg/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 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 oxytetracyline 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
- Oxytetracycline 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 oxytetra-
cycline. Thus, all toxicological data requirements have been waived.
- 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
- 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 pm 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
- 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 determined to be 10000 ppm, approximately 250 mg/kg/day, highest
NI/NTP Oxytetracycline oncogenicity 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. The National Toxicology Program
concluded that ". . . . there was equivocal evidence(1) of
carcinogenicity for male F344/N 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 Oxytetracycline Oncogenicity Study in the B6C3Fl Mouse
In this study, oxytetracycline hydrochloride (purity 98.8) was
administered to groups of B6C3Fl 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
B6C3Fl mice fed diets containing 6300 or 12500 ppm of oxytetracycline
hydrochloride for 2 years."
Female Charles River CD rats were dosed during days 6 through 15 of
gestation with 1200, 1350, or 1500 mg/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 LEL 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
Female CD-l 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/NTP 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 of carcinogenicity, (ii) some evidence of
carcinogenicity, (iii) equivocal evidence of carcinogenicity, (iv) no
evidence of carcinogenicity, and (v) inadequate study of
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. TOLERANCE 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 FDA
according to 21 CFR 520, 522, 524, and 558. The FDA has established
tolerances for oxytetracycline in or on meat, fat, meat byproducts, and
in uncooked edible tissues of salmonoid fish and catfish (21 CFR
No data are available to evaluate the nature of the residue of
oxytetracycline in plants. The Agency has assessed the need or data
reflecting the metabolism of oxytetracycline in plants and has concluded
that these data are not required because of the drug uses of
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
- 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 pm.
- The Agency will not propose the establishment of crop group tolerances
for pome fruits or stone fruits.
- 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 submitted 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 MAJOR DATA GAPS
Environmental fate/Exposure:(2) Submission
Hydrolysis 9 Months
Photodegradation in water and in soil 9 Months
Metabolism studies (lab)
-Aerobic soil 27 Months
-Anaerobic Soil 27 Months
-Anaerobic Aquatic 27 Months
-Aerobic Aquatic 27 Months
Leaching and Adsorption/Desorption 12 Months
Dissipation Studies (field)
-Soil 27 Months
-Aquatic (Sediment) 27 Months
Accumulation in Fish 12 Months
Fish & Wildlife:
Avian Acute Oral LD50 9 Months
Avian Dietary LC50 9 Months
Freshwater Fish LC50 (TGAI)(3) 9 Months
Freshwater Invertebrate (TGAI) 9 Months
All product chemistry studies 9 Months
(2) Environmental Fate data requirements only for calcium
(3) IPI: Technical grade of the active ingredient
7. CONTACT PERSON AT EPA
Product Manager (21)
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
DISCLAIMER: 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