PUBLICLY RELEASABLE SUMMARY OF THE PETITION 

FOR ESTABLISHMENT OF A TOLERANCE 

FOR RESIDUES OF OXYTETRACYCLINE 

IN OR ON AGRICULTURAL COMMODITIES, 

CITRUS FRUITS, GROUP 10 -10 

 
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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Hope Johnson, 

703-305-5410, johnson.hope@epa.gov, PM Team 21

Geo Logic Corp. 

PP 5F8415

EPA has received a pesticide petition (PP#5F8415) from Geo Logic Corp. PO 

Box 3091, Tequesta, FL 33409 requesting, pursuant to section 408(d) of the Federal 

Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 

180 by establishing a tolerance for residues of oxytetracycline in or on the raw 

agricultural commodities, citrus, Crop Group 10-10, at 0.01 ppm. Geo Logic 

Corp. proposes 1) the modifications of the tolerance expression for oxytetracycline in 

paragraph (a) in 40 CFR 180.337 as shown below. 

(a) General. (1) Tolerances are established for residues of the fungicide 

oxytetracycline, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only 

oxytetracycline (4S,4aR,5S,5aR,6S,12aS)-4-(dimethylamino)-

1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-

dioxo-2-naphthacenecarboxamide in or on the commodity. 

Commodity Parts per million 

Apple 0.35

Peach 0.35

Pear 0.35

Citrus (Crop Group 10-10) 0.01 

EPA has determined that the petition contains data or information regarding the elements 

set forth in section 408 (d) (2) of FFDCA; however, EPA has not fully evaluated the 

sufficiency of the submitted data at this time or whether the data supports granting of the 

petition. Additional data may be needed before EPA rules on the petition. 

A. Residue Chemistry

1. Plant metabolism. EPA stated in the Oxytetracycline HED Chapter of the TRED

and proposed new uses on apples (February 7, 2006) that plant (and animal) metabolism 

data were not needed due to its widespread use as a drug, and low residue levels expected 

in or on tree fruit. In EPA’s Registration Standard (Dec 1988) the residue of concern was 

determined to be oxytetracycline, only, as specified in 40 CFR 180.337; and the 

Toxicology Branch concluded that data on the nature of the residue in plants are not 
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required. 

2. Analytical method. Citrus samples were analyzed for oxytetracycline using a

laboratory working method based on extraction using acidified methanol, and analysis by 

reversed-phased liquid chromatography with detection by MS/MS spectrometry (LCMS/MS). Confirmation is accomplished by comparison of retention time and selective 

reaction monitoring (SRM) MS/MS spectra with those of fortified samples and external 

standards. The LOQ has been demonstrated to be 0.01 ppm. 

3. Magnitude of residues.

Citrus 

The magnitude of residues of oxytetracycline was determined in representative 

commodities of citrus, Crop Group 10-10. The raw agricultural commodity (RAC) matrix 

of whole fruit and the processed commodities of orange peel, orange oil, orange dried pulp, 

and orange juice were analyzed following three foliar applications of FireLine 17 WP 

targeting a 21-day spray interval and a 60-day pre harvest interval (PHI). The samples 

harvested for determination of residue in the RAC whole fruit were treated with three 

applications of approximately 0.27 pounds active ingredient per acre (lb.ai/A) or 

approximately 0.81 lb. ai/A/season. For determination of residues in the processed 

commodities, at one trial location, a second treated plot of oranges was treated at a 3x rate 

of three applications targeting 0.81 lb ai/A or 2.43 lb. ai/A/season. 

FireLine 17 WP is a broad spectrum fungicide/bactericide formulated as a wettable powder 

(WP) which nominally contained 18.3% of the active ingredient, oxytetracycline 

hydrochloride. Spray volumes were targeted at approximately 100 gallons per acre (GPA). 

Field trials were conducted at twenty four locations representing the major commercial 

citrus (Crop Group 10) growing regions in the USA. Thirteen orange trials were 

conducted: nine trials in EPA Region 3 (Florida), one trial in Region 6 (Texas), and three 

trials in Region 10 (California). Six grapefruit trials were conducted: three trials in EPA 

Region 3 (Florida), one trial in Region 6 (Texas), and two trials in Region 10 (California). 

Five lemon trials were conducted: one trial in EPA Region 3 (Florida) and four trials in 

Region 10 (California). 

The raw agricultural commodities (RAC) of orange, lemon, and grapefruit whole fruit were 

selected in accordance with US EPA Residue Chemistry Test Guidelines, OPPTS 

860.1500. The processed commodities of orange peel, orange oil, orange dried pulp, and 

orange juice are in accordance with US EPA Residue Chemistry Test Guidelines, OPPTS 

860.1520. 

Orange, lemon, and grapefruit were harvested at typical commercial maturity for residue 

analysis. Each RAC trial included an untreated plot which produced a single composite 

sample and one treated plot which yielded duplicate composite whole fruit samples. In 

addition, bulk whole fruit samples were collected from a second treated plot located at Trial 

09. This treated plot (T2) had three applications at a 3x rate (0.81 lb ai/A) for the purpose
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of producing whole fruit to be processed into the commodities of orange peel, orange oil, 

orange dried pulp, and orange juice. 

Actual application rates ranged from 0.262 - 0.276 lbs ai/A for the 1x, RAC, treated plot 

(T1) and 0.809 - 0.810 lbs ai/A for the 3x rate, processing treated plot (T2). Actual spray 

volumes ranged from 91.3 – 108.5 gallons per acre. Each treated plot received three 

applications sprayed at 21 day spray intervals. Applications were targeted so that normal 

harvest of whole fruit would occur approximately 60 days after the last application. At one 

orange site (Trial 08) and one grapefruit site (Trial 13), samples of whole fruit were 

collected at 40±2, 50±2, 60±2, 70±2, and 80±2 days after the last application (DALA) in 

order to determine a potential residue decline profile. 

Citrus RAC and processed samples were maintained frozen after collection through 

analysis for up to 208 days. Samples were prepared for analysis by chopping and 

homogenizing the entire field sample, then removing a subsample for analysis. 

Subsamples were maintained frozen from receipt until extraction for analysis. 

Residues of the active ingredient, oxytetracycline hydrochloride, were determined using 

the analytical method, “Analytical Method for the Assay of Oxytetracycline Residues in 

Citrus and Citrus Processed Fractions”. The limit of quantitation (LOQ) and limit of 

detection (LOD) were set at the initiation of the analytical phase of the study at 0.01 ppm 

and 0.002 ppm, respectively, for oxytetracycline. The overall mean concurrent recoveries 

for oxytetracycline from citrus whole fruit, citrus whole fruit without the peel, citrus peel, 

orange oil, orange dried pulp, and orange juice were 107 ± 9% (n = 14), 114 ± 3% (n = 8), 

105 ± 10% (n = 12), 83 ± 16% (n = 2), 116 ± 3 (n = 2), and 88 ± 3% (n = 2), respectively. 

Following 3 applications of approximately 0.27 lb. ai/A, no residues of oxytetracycline 

were detected (ND = <0.002 ppm) in citrus RAC whole fruit and whole fruit without peel 

control and treated samples. Residues were ND (<0.002 ppm) for all RAC peel samples 

with the exception of sample, OTC-15-003, which was <LOQ (0.01 ppm). Residues for all 

decline whole fruit samples were ND (<0.002 ppm). 

Following three applications of approximately 0.81 lb. ai/A, no residues of oxytetracycline 

were detected (ND = <0.002 ppm) in orange dried pulp, orange juice, orange whole fruit, 

and orange peel samples. Residues of oxytetracycline in orange oil ranged from ND 

(<0.002 ppm) to <LOQ (0.01 ppm). 

The agronomic and environmental field conditions experienced during the course of this 

study were representative of typical commercial farming practices for citrus. All 

representative residues were below the limit of quantitation. The treatment regime in this 

study represents the maximum rate, shortest retreatment interval, maximum number of 

applications, and shortest PHI expected for the product label. Therefore the residue values 

obtained during this study are likely to exceed those in actual commercial cropping 

situations for the proposed use pattern for oxytetracycline hydrochloride in/on citrus crop 

group 10-10. 
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B. Toxicological Profile 

EPA has noted in the Oxytetracycline HED Chapter of the TRED and Proposed New Uses 

on Apples (February 7, 2006) that oxytetracycline is a broad-spectrum antibiotic used to 

treat bacterial, fungal and mycoplasma-like organism infections in humans and animals. 

As a result of the uses as a human and animal drug, there is an extensive body of 

toxicological data available on oxytetracycline. Thus, all toxicological data requirements 

have been waived. No acute dietary risk assessment has been conducted because no acute 

toxicity was identified in any of the relevant studies in the oxytetracycline database. 

Further, it was noted that EPA has evaluated the aggregate risks from the supported 

registered uses and the results indicate that chronic aggregate dietary exposure to 

oxytetracycline from food and drinking water is below HED’s level of concern for the 

general population and all population sub-groups. In regard to the cumulative risk of 

oxytetracycline, EPA stated the following in the Oxytetracycline TRED: “Unlike other 

pesticides for which EPA has followed a cumulative risk approach based on a common 

mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 

oxytetracyclne and any other substances, and oxytetracycline does not appear to produce a 

toxic metabolite that is also produced by other substances. Therefore, EPA has not assumed 

that oxytetracycline has a common mechanism of toxicity with other substances”. 

The following is relevant available toxicological information on oxytetracycline. 

1. Acute toxicity. In mice, oxytetracycline has a low acute toxicity, being a 

Category IV for oral toxicity (LD50 >7,200 mg/kg). The acute toxicity of the 

FireLine 17 WP formulation of oxytetracycline hydrochloride is summarized 

in the following table: 

2. Genotoxicty. Oxytetracycline exhibited negative to weakly positive results in 

a series of genetic toxicity tests to determine its potential to interact with DNA 

or damage chromosomes-indicating that it is unlikely to cause cancer. 

Route of application Animal FireLine 17 WP formulated 

product 

Oral LD 50 Rat >5,000 mg/kg 

Dermal LD 50 Rat >5,000 mg/kg 

Inhalation LC 50 Rat >2.09 mg/L air – 4 hours 

Eye irritation Rabbit Mildly irritating (FlameOut 20WP) 

Skin sensitization Guinea pig No evidence of sensitization observed
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3. Reproductive and developmental toxicity. According to the EPA TRED report 

dated June 2006, there was no evidence of increased sensitivity in pups versus 

adults based on rat and mouse developmental studies and the rat multigeneration study. In pre-natal developmental studies in both rats and mice 

treated with oxytetracycline, there was no toxicity identified in the pups at any 

dose tested. In the two-generation study, there was no toxicity identified in 

pups at the highest dose tested (18 mg/kg/day). 

4. Subchronic toxicity. The February 7, 2006 Oxytetracycline: HED chapter for 

the TRED reports a 3 month mouse study was conducted at doses ranging from 

465 to 7,500 mg/kg/day. The NOAEL was 3,750 mg/kg/day. A 3 month rat 

study was also conducted at doses ranging from 155 to 2,500 mg/kg/day. The 

NOAEL was 2,500 mg/kg/day. The highest dose tested. 

5. Chronic toxicity. Two 2-year chronic toxicity studies in rats are available. In 

one study, Osborne-Mendel rats were fed diets containing 0, 100, 1,000, and 

3,000 ppm, oxytetracycline hydrochloride in the diet for 24 months. The 

NOEL was determined to be 3,000 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 1,000 pm oxytetracycline hydrochloride in the 

diet for 24 months. The NOEL for oxytetracycline hydrochloride was 1,000 

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, 3,000, and 10,000 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 10,000 ppm, 

approximately 250 mg/kg/day, highest dose tested. 

 

In a second study, mongrel dogs were fed diets containing 0, 5,000 and 10,000 

of oxytetracycline hydrochloride in the diet for 12 months. The NOEL 

determined to be 10,000 ppm, approximately 250 mg/kg/day, highest dose 

tested. No evidence of carcinogenicity was found in a literature search 

 of toxicity in animals or humans. 

A special antimicrobial resistance study in dogs was performed. Mature 

beagles were fed a ground-meal diet containing 0, 2, or 10 ppm of 

oxytetracyline for 44 days. The 10 ppm (0.25 mg/kg/day) diet resulted in a 

shift from a pre-dominantly drug-susceptible population of enteric lactosefermenting organisms to a multiple antibiotic-resistant population. The 

NOAEL was 0.05 mg/kg/day. The chronic endpoint was based on the 

microbiologic study in dogs and is conservative and protective for the entire 

toxicological data base. 

 6. Carcinogenicity. There is carcinogenic potential, but no evidence of 
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carcinogenicity was observed in rats. In F344/N rats, histological examination 

showed a dose related increase of benign phaeochromcytomas in the adrenal 

gland of male rats fed 2,500 mg/kg/day. In females an increase in incidence of 

adenomas of the pituitary gland was found in the highest dose group (1,875 

mg/kg/day). Mice fed up to 1,875 mg/kg/day exhibited no evidence of 

carcinogenicity. 

7. Animal metabolism. The Agency has determined, and stated in the EPA 

Oxytetracycline HED Chapter of the TRED and proposed new uses on apples 

(February 7, 2006) that animal metabolism data were not needed because of its 

widespread use as a drug, and low residues expected on crops. The residue of 

concern is the parent compound, oxytetracycline.

8. Metabolite toxicology. Oxytetracycline undergoes minimal metabolism in the 

environment, as well as in crops, animals and humans. The nature of the residue 

in plants and animals is adequately understood; the residue of concern is 

oxytetracycline for plants and water. No quantifiable residues of oxytetracycline 

are expected in livestock commodities. Due to the wide use of oxytetracycline 

as a human drug, and to the low residue levels expected in/on raw agricultural 

commodities (RACs), no metabolism data have been required.

9. Endocrine disruption. No specific information available. No cited evidence in 

existing toxicological studies. 

C. Aggregate Exposure

1. Dietary exposure. 

i. Food and ii. Drinking water. EPA did not conduct acute dietary assessments 

because no acute toxicity endpoint could be identified based on data currently 

available for oxytetracycline. As part of the TRED, EPA did a chronic dietary 

and drinking water assessment for uses on apples, peaches, pears and nectarines 

using the Dietary Exposure Evaluation Model (DEEM-FCIDTM), Version 2.03 

(DP No. D310391, 1/9/06). The drinking water component was based on EPA’s 

evaluation of potential surface and ground water residues modeled with FIRST 

(surface water) and SCI-GROW (ground water). The highest Estimated 

Drinking Water Concentrations (EDWCs) values reflected the maximum use 

pattern for oxytetracycline (on peaches and nectarines). The highest chronic 

estimated drinking water concentration obtained in surface water (4.6 ppb) was 

selected as a point estimate in the aggregate dietary + drinking water analysis 

of oxytetracycline. 

To support the new use of FireLineTM 17 WP on citrus, a dietary and drinking 

water exposure and risk assessment with the current crop uses plus citrus was 

performed using DEEM-FCID version 4.02 and citrus residue data from recent 

citrus field studies treated with three foliar applications of FireLine 17 WP at 
8

0.27 lb AI/A, each application. No residues (LOQ=0.01 ppm) were found in 

whole fruit, juice, oil or dried pulp in crop residue trials. Geo Logic Corp. has 

proposed the NAFTA MRL (citrus fruit: 0.01 ppm) as tolerances. 

Assumptions for this analysis were: 100 percent citrus crop is treated; deciduous 

fruit residues from EPA documents; percent crop treated for the deciduous tree 

fruits from a 2011 National Agricultural Statistics Service survey; the EPAidentified chronic surface water concentration for drinking water (as described 

above); and, percent crop area in the watershed identified by EPA for orchards 

in a 2014 guidance document. The chronic assessment was done using the 

EPA-identified chronic population adjusted dose, cPAD, (the same as the 

reference dose, RfD) for all subpopulations in the DEEM. The RfD was based 

on 10X intraspecies, 10X interspecies and 1X FQPA uncertainty factors: 0.0005 

mg/kg based on a no observed adverse effect level of 0.05 mg/kg in an oral dog 

study of the induction of antibiotic resistance in gut bacteria. Under the 

conditions modeled, the total U.S. population exposure was 11% of the cPAD. 

The most highly exposed subpopulation was non-nursing infants at 61% of the 

cPAD. Since all population exposures were less than 100% of the cPAD, no 

additional refinements were necessary. 

Based on this screening level assessment of adding citrus uses, and the results 

which demonstrate the citrus commodity contribution as a % of the cPAD is 

0.1%, the EPA should have no concerns about excess risk.

2. Non-dietary exposure. There are no anticipated exposures in or around homes 

or recreational areas. 

D. Cumulative Effects 

EPA has stated the following in the Oxytetracycline: HED Chapter of the TRED (EPA DP 

Barcode D315684; Case No. 0655, Feb 7, 2006): Unlike other pesticides for which EPA 

has followed a cumulative risk approach based on a common mechanism of toxicity, EPA 

has not made a common mechanism of toxicity finding as to oxytetracycline and any other 

substances, and oxytetracycline does not appear to produce a toxic metabolite that is also 

produced by other substances. Therefore, EPA has not assumed that oxytetracycline has a 

common mechanism of toxicity with other substances, including metabolites. 

E. Safety Determination

1. U.S. population. There is no residential use on the oxytetracycline label- thus 

there is no residential exposure to aggregate with the chronic dietary exposure for the U.S. 

population of 0.000053 mg/kg/day. When compared to a human therapeutic dose of 1-2 g 

per day for adults, the above noted dietary exposures would have minimal impact and cause 

no harm. 
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2. Infants and children. The chronic dietary exposure for non-nursing infants is 

0.000305 mg/kg/day. When compared to a human therapeutic dose of 25-50 mg/kg/day for 

children, the above noted dietary exposures would have minimal impact and cause no harm. 

F. International Tolerances

No available information.