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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; 
  Oxytetracycline hydrochloride
- Chemical Name: 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-
  3,5,6,10,12,12a-hexahydro-6-methyl-1,ll-dioxo-2-naphthacenecarboxamide
  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
  rimosus)
- Pesticide Type:  Plant Fungicide/Bactericide and Algicide
- CAS Registry Number:   79-57-2  (oxytetracycline)
                         7179-50-2   (calcium complex)
                         2058-46-0   (hydrochloride)
- EPA Shaughnessy Codes: 006304  (oxytetracycline)
                         006321 (calcium complex)
                         006308  (hydrochloride)
- 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
  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. 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
  use).


                       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 
available.


Toxicology Characteristics

- 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.


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 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
  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 determined to be 10000 ppm, approximately 250 mg/kg/day, highest
  dose tested.


Oncogenicity

     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."


Teratogenicity

     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 
treated dams.

     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 
carcinogenicity.


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 
556.500).

     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 
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 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

                                                       Timeframe for
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

Product Chemistry

All product chemistry studies                            9 Months

____________

(2) Environmental Fate data requirements only for calcium
    oxytetracycline.
(3) IPI: Technical grade of the active ingredient


                    7. CONTACT PERSON AT EPA

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


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 
information.