PUBLICLY RELEASABLE SUMMARY OF THE PETITION

FOR ESTABLISHMENT OF A TOLERANCE

FOR RESIDUES OF O XYTETRACYCLINE IN OR ON AGRICULTURAL COMMODITIES, CITRUS FRUITS, GROUP 10 -102

EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division conta ct: 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 Co rp. PO

Box 3 0 9 1

, Tequesta, FL 33409 reques ting, pursuant to sect ion 40 8(d) of the Federal Food, Drug, and Cosmetic Act (FFD CA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for re sidues of oxytetracyc line in or on th e raw

ag r icultural commodities, citr us, Crop Gr oup 10-10, at 0.01 ppm. Geo Lo g ic

C o r p. p r oposes 1) the modifications of the tolerance expression for o x y tetr acyclin e in

p aragraph (a) in 40 CFR 180.337 as shown below.

(a) General. (1) Tolerances are establ ished 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 determ ined that the petition contains data or information re garding 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 tim e 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 re sidue levels expected

in or on tree fruit. In EPA’ s Registration Standard (Dec 1988 ) the residue of concern was determined to be oxytetracycline, onl y, as specified in 40 CFR 180.337; and the Toxicology Branch concluded that data on the nature of the residue in plants are not3

required.

2. Analytical method. C itrus samples were analyzed for oxytetracycline using a laboratory working method based on extraction us ing acidified methanol , and analysis by reversed-phased liquid chromatography with detection by MS/MS spectrometry (LCMS/MS). Confirmation is accomplished by comp arison 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 oxytetracy cline was determined in representative commodities of citrus, Crop Group 10-10. The ra w 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 th ree foliar applications of FireLine 17 WP targeting a 21-day spray interv al and a 60-day pre harvest in terval (PHI). The samples

harvested for determination of residue in the RAC whole fruit were treated with three applications of approximately 0.27 pounds ac tive ingredient per acre (lb.ai/A) or approximately 0.81 lb. ai/A/seas on. For determination of residues in the processed commodities, at one trial location, a second treate d 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 sp ectrum fungicide/bactericide form ulated as a wettable powder (WP) which nominally contained 18.3% of the active ingredient, oxytetracycline hydrochloride. Spray volumes were targeted at approximately 100 gallo ns per acre (GPA).

Field trials were conducted at twenty four locations repr esenting the major commercial citrus (Crop Group 10) growing regions in th e 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 conducte d: one trial in EPA Region 3 (F lorida) and four trials in Region 10 (California).

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

selected in accordance with US EPA Re sidue 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 untre ated 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 applicatio ns at a 3x rate (0.81 lb ai/A) for the purpose4

of producing whole fruit to be processed into the commodities of orange peel, orange oil, orange dried pulp, and orange juice.

Actual application rates range d from 0.262 - 0.276 lbs ai/A fo r 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 acr e. Each treated pl ot received three applications sprayed at 21 day spray intervals. Applications were targeted so that normal

harvest of whole fruit would o ccur approximately 60 da ys after the last a pplication. At one orange site (Trial 08) and one grapefruit si te (Trial 13), samples of whole fruit were collected at 40±2, 50±2, 60±2, 70±2, and 80±2 da ys after the last application (DALA) in order to determine a potentia l 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 fr om receipt until extraction for analysis.

Residues of the active ingredie nt, 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 th e 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, citr us 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 RA C whole fruit and whol e fruit without peel control and treated samples. Residues we re ND (<0.002 ppm) for all RAC peel samples with the exception of sample, OTC-15-003, wh ich 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 dr ied pulp, orange juice, orange whole fruit, and orange peel samples. Residues of oxytet racycline in orange oil ranged from ND (<0.002 ppm) to <LOQ (0.01 ppm).

The agronomic and environmental field conditi ons experienced during the course of this study were representative of typical commer cial farming practices for citrus. All representative residues were belo w 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 th e product label. Theref ore the residue values obtained during this study are likely to exceed those in actual commercial cropping situations for the proposed us e pattern for oxytetracycline hyd rochloride in/on citrus crop group 10-10.5

B. Toxicological Profile

EPA has noted in the Oxytetracycline HED Ch apter of the TRED and Proposed New Uses on Apples (February 7, 2006) that oxytetracycl ine is a broad-spectru m antibiotic used to treat bacterial, fungal and mycoplasma-like or ganism 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 to xicological data requirements have been waived. No acute dietary risk as sessment has been conducted because no acute toxicity was identified in any of the releva nt studies in the oxytetracycline database. Further, it was noted that EPA has evalua ted the aggregate risks from the supported registered uses and the results indicate th at 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 rega rd to the cumulative risk of oxytetracycline, EPA stated the following in the Oxytetracycline TRED: “Unlike other pesticides for which EPA has followed a cu mulative risk appro ach based on a common mechanism of toxicity, EPA has not made a co mmon mechanism of toxi city finding as to oxytetracyclne and any other substances, and oxytetracycline does not appear to produce a toxic metabolite that is also produced by othe r substances. Therefore, EPA has not assumed that oxytetracycline has a common mechanism of toxicity with other substances”.

The following is relevant available toxi cological informati on on oxytetracycline.

1. Acute toxicity. In mice, oxytetracycline has a low acute toxicity, being a Category IV for oral toxicity (LD 50 >7,200 mg/kg). The acute toxicity of the FireLine 17 WP formulation of oxytetra cycline hydrochloride is summarized in the following table:

2. Genotoxicty. Oxytetracycline exhibited negative to weakly positive results in a series of genetic toxicity tests to dete rmine 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 observed6

3. Reproductive and developmental toxicity. According to the EPA TRED report dated June 2006, there was no evidence of increased sensitivity in pups versusadults based on rat and mouse developmental studies and the rat multigeneration study. In pre-natal developmen tal studies in both rats and mice treated with oxytetracycline, there was no toxicity iden tified 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 Oxytetr acycline: 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 wa s 3,750 mg/kg/day. A 3 month rat study was also conducted at doses ra nging 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 pp m, approximately 150 mg/kg/body weight/day, highest dose tested. In a s econd study, Sprague Dawley rats were fed diets containing 0, 100, and 1,000 pm oxytetracycline hydroc hloride in the diet for 24 months. The NOEL for oxyt etracycline 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 th e 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 fe d 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, appr oximately 250 mg/kg/day, highest dose tested. No evidence of carcinogenic ity was found in a literature search of toxicity in animals or humans.

A special antimicrobial resistance st udy 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-suscep tible population of enteric lactosefermenting organisms to a multiple antibiotic-resistant population. The NOAEL was 0.05 mg/kg/day. The chroni c endpoint was based on the microbiologic study in dogs and is conser vative and protective for the entire toxicological data base.

6. Carcinogenicity. There is carcinogenic potentia l, but no evidence of7

carcinogenicity was observed in rats. In F344/N rats, histological examination

showed a dose related increase of beni gn 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 wa s 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 TR ED 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 resi dues expected on crops. The residue of concern is the parent compound, oxytetracycline.

8. Metabolite toxicology. Oxytetracycline undergoes mi nimal 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 coul d be identified base d 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-FCID TM ), 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 a nd 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 FireLine TM 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 an d citrus residue data from recent

citrus field studies treated with three fo liar applications of FireLine 17 WP at8

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 fr uit: 0.01 ppm) as tolerances. Assumptions for this analysis were: 100 percent citrus cr op is treated; deciduous fruit residues from EPA documents; percen t crop treated for the deciduous tree fruits from a 2011 National Agricultural Statistics Service survey; the EPAidentified chronic surface water concen tration for drinking water (as described above); and, percent crop area in the watershed iden tified by EPA for orchards in a 2014 guidance document. The chronic assessment was done using the EPA-identified chronic population adjust ed dose, cPAD, (the same as the reference dose, RfD) for all subpopulati ons in the DEEM. The RfD was based on 10X intraspecies, 10X interspecies a nd 1X FQPA uncertainty factors: 0.0005 mg/kg based on a no observed adverse eff ect level of 0.05 mg/kg in an oral dog study of the induction of antibiotic resi stance in gut bacteria. Under the conditions modeled, the total U.S. populat ion exposure was 11% of the cPAD. The most highly exposed subpopulation was non-nursing infant s at 61% of the cPAD. Since all population exposures we re 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 e xposures in or around homes

or recreational areas.

D. Cumulative Effects

EPA has stated the following in the Oxytetracy cline: 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 ba sed 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 ot her substances, including metabolites.

E. Safety Determination

1. U.S. population. There is no residential use on th e oxytetracycline label- thus there is no residential exposure to aggregate w ith 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 e xposures would have minimal impact and cause

no harm.9

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 dietar y exposures would have minima l impact and cause no harm.

F. International Tolerances

No available information.