PUBLICLY RELEASABLE SUMMARY OF THE PETITION

FOR ESTABLISHMENT OF A TOLERANCE

FOR RESIDUES OF STREPTOMYCIN IN OR ON AGRICULTURAL COMMODITIES, CITRUS FRUITS, GROUP 10 -102 EP A REGISTRATION DIVISION CO MPANY 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.

P esticide Petition Number 5F8427

EPA has received a pesticide petition ( PP# 5 F8427 ) from Geo Logic Corp. PO Box 3091, Tequesta, FL 33409 requesting, pursuant to section 40 8(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 2 1 U.S. C. 346 a(d), to amend 40 CFR part 1 8 0 b y establishing a tolerance for residues of st reptomycin in or on th e raw

ag r icu ltural co mmo dities citrus fruit , Crop Group 10-10, at 0

. 5 ppm, and citrus, dried

p u lp at 3.5 ppm. Geo Lo g ic Co rp. proposes 1) the modifications of the tolerance expression for strep to my cin in paragraphs (a)(1), (a)(2) and (a)(3) in 40 CFR 180.245

as shown below and p r o poses 2) the removal of th e time lim ited to ler ances fo r

g r ap efr u it and grapefruit d r ied pulp in paragraph 3(b) of 40 CFR 1 8 0

. 2 4 5 u p o n approval

o f th e r e q u ested tolerances for citrus and citrus dried pulp.

(a) General. (1) Tolerances are established for residues of the f ungicide/bactericide streptomycin, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tole rance levels specified below is to be determined by measuring only streptom ycin (O-2-Deoxy-2-(methylamino)-a-Lglucopyranosyl-(1-2)-O-5-deoxy-3-C-fo rmyl-a-L-lyxofura nosyl-(1-4)-N,N’- bis(aminoiminomethyl)-D-streptam ine) in or on the commodity.

Commodity Established Tolerance Parts per million (ppm) Bean, dry, seed 0.5
Bean, succulent 0.5 Fruit pome, group 11-10 0.25

(2) Tolerances are established for residues of the fungicide/bacte ricide streptomycin,

includ ing its metabolites and degradates, from treatment of seedling plants before transplanting, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only streptomycin (O-2-Deoxy-2-(methylamino)-a-L-glucopyr anosyl-(1-2)-O-5-deoxy-3-C-formyl-aL- lyxofuranosyl-(1-4)-N,N’-bis(aminoimino methyl)-D-streptami ne) in or on the commodity.3 (3) Tolerances are established for residues of the fungicide/bacte ricide streptomycin, including its metabolites and degradates, from treatment of seed pieces, in or on the commodities in the table below. Complian ce with the tolerance levels specified below is to be determined by meas uring only streptomycin (O-2-Deoxy-2- (methylamino)-a-L-glucopyranosyl-(1-2)-O -5-deoxy-3-C-formyl-a-L-lyxofuranosyl- (1-4)-N,N’-bis(aminoiminomethyl)-D-stre ptamine) in or on the commodity.

Commodity Established Tolerance Parts per million (ppm)

Potato 0.25

(4) Tolerances are proposed for residues of the fungicide/bactericide streptomycin, including its metabolites a nd degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only streptomycin (O-2-Deoxy- 2-(methylamino)-a-L-glucopyranosyl-(1- 2)-O-5-deoxy-3-C-formyl-a-L-lyxofura nosyl-(1-4)-N,N’-bis(a minoiminomethyl)-Dstreptamine) in or on the commodity.

Commodity Proposed Tolerance Parts per million (ppm) Citrus, group 10-10 0.5 Citrus, dried pulp 3.5

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. A dditional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The Agency has determined, and stated in the EPA Streptomycin Pesticide Fact Sheet (September, 1988) that plant (and animal) metabolism data were not needed for the following reasons:

i. Metabolism of streptomycin in ma mmals has already been traced

in connection with its use in humans;

ii. Residues are non-detectable (<0.5 ppm) in or on crops when treated Commodity Established Tolerance Parts per million (ppm) Celery 0.25 Pepper 0.25

Tomato 0.254 according to label use rates and directions;

iii. Large amounts of toxi cological data exist;

iv. Most crops are treated at or befo re transplanting (celery, peppers, potatoes, tomatoes) and pome fruits are treated foliarly but with a 30-day PHI for pears and a 50-day PHI for apples and crabapples;

v. Potential daily exposure to streptom ycin as a pesticide is <0.01% of the daily clinical do sage (1-4 grams/day).

2. Analytical method. Citrus s amples were analyzed for streptomycin using a laboratory working method based on USDA Food Safety and Inspection Service SOP No: CLG-AMG1.02, “Confir mation of Aminoglycosides by HPLC-MS/MS”. Modifications were made to improve the performance of the method for the various crop fractions.

The analytical method used to determine residues of streptomycin was

based on “Analytical Method for the Assay of Streptomycin 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 pp m, respectively, for streptomycin in all matrices except for dried pulp whic h had an LOQ of 0.05 ppm and an LOD of 0.01 ppm. A summary of the method is as follows.

Streptomycin residues were extracted from citrus using pH 4 (whole fruit and dried pulp) potassium phosphate buffer containing both pectinase and cellulase. The extract was filtered to remove crop solids. Cleanup was accomplished by passage through a C8-solid-phase extraction cartridge. The pH of the eluate from the C8 co lumn was adjusted to ~ pH 8 and the eluate further cleaned by loading onto a weak cation exchange (CBX) solid-phase extraction cartridge. The CBX cartridge was eluted with 1% formic acid/ methanol(whole fruit) or 2% formic acid/methanol (dried pulp). The methanolic eluates were th en evaporated and reconstituted in

0.1% formic acid in water. The recons tituted residues were then analyzed by ion-pair reversed-phase liquid chromatography with detection by MS/MS spectrometry. Confirmation was accomplished by comparison of retention time and selective reaction monitoring (SRM) MS/MS spectra

with those of fortified citrus and external standards.

Analytical sets typically consisted of calibration standards, unfortified controls, fortified controls, and treated samples. The linearity of the instrument response over the expected range of residues was confirmed with each analysis set. The effici ency of the analytical method was determined at the time of analysis w ith each set of samples by fortifying subsamples of the control citrus ma trix, processing them according to the analytical method, and analyzing them similar to a field-treated sample. Control matrices fortified at appr oximately the LOQ (0.01 ppm or 0.05 ppm) and 10 times the LOQ (0.10 ppm or 0.50 ppm) were typically5 included in the analysis set for me thod verification. The methodology was shown to be robust for citrus samples.

3. Magnitude of residues. The magnitude of residues of streptomycin was determined in representative commod ities of citrus, Crop Group 10-10 following applications of FireWall 50 WP (streptomycin sulfate). The RAC matrix of whole fruit and the pr ocessed commodities of orange peel, orange oil, orange dried pulp, and or ange juice were analyzed following three foliar applications of Fire Wall 50 WP targeting a 21-day spray interval and a 60-day PHI. In addition to whole fruit, additional fruit were separated into whole fruit without peel (flesh) and peel which were analyzed separately

. The samples harvested for determination of residue in

the RAC whole fruit were treated with three applications of approximately 0.452 pounds active ingredient per acre (lb. ai/A) or a pproximately 1.356

lbs. ai/A/season. For determinat ion 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 target ing 1.356 lbs. a i/A or 4.068

lbs. ai/A/season.

FireWall 50 WP is a broad spectrum fungicide/bactericide formulated as a wettable powder (WP) which nomina lly contained 65.8% of the active ingredient, streptomycin sulfate, e quivalent to 50% streptomycin. Spray volumes were targeted at approxim ately 100 gallons per acre (GPA).

Field trials were conducte d at twenty-four locations repres enting the major commercial citrus (Crop Group 10-10) growing regions in the USA. Thirteen orange trials were conduc ted: nine trials in EPA Region 3 (Florida), one trial in Region 6 (Texas), and three trials in Region 10 (California). Six grapefruit trials we re conducted: three trials in EPA Region 3 (Florida), one trial in Region 6 (Texas), and two trials in Region 10 (California). Five lem on 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 accord ance with US EPA Residue Chemistry Test Guidelines, OPPTS 860.1500. The pr ocessed commodities of orange peel, orange oil, orange dried pulp, an d orange juice are in accordance with US EPA Residue Chemistry Te st 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 sec ond treated plot located at Trial 09. This treated plot (T2) had three app lications each at a 3x rate (1.356 lbs. ai/A) for the purpose of producing whol e fruit to be processed into the6 commodities of orange peel, orange oil, orange dried pulp, and orange juice.

Actual application rates ranged from 0.447 - 0.462 lb. ai/A for the 1x, RAC, treated plot (T1) and 1.35 – 1.36 lbs. a i/A for the 3x rate, processing treated plot (T2). Actual spray volumes range d from 91 – 109 gallons per acre. Each treated plot received three app lications sprayed at a target 21-day spray interval. Applications were targ eted so that normal harvest of whole fruit would occur approximately 60 days after the last appl ication. At one orange site (Trial 08) and one grapef ruit site (Trial 13), samples of whole

fruit were collected at 40, 50, 62, 70, and 80 days af ter 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 214 days. Samples were prepared for analysis by chopping and homogenizing the enti re field sample, then removing a subsample for analysis. Subsamples were maintained frozen from receipt until extraction for analysis. Residues of streptomycin were determined using the analytical method, “ Analytical Method for Streptomycin

Residues in Citrus and Citr us Processed Fractions”. The limit of quantitation (LOQ) and limit of detec tion (LOD) were set at the initiation of the analytical phase of the study at 0.01 ppm and 0.002 ppm, respectively, for streptomycin in all matrices except orange dried pulp which had an LOQ/LOD of 0.05/0.01 ppm. The overall mean concurrent recoveries for streptomycin from citr us whole fruit, citrus whole fruit without the peel, citrus peel, orange o il, orange dried pulp, and orange juice were 97 ± 16% (n = 18), 89 ± 10% (n = 10), 81 ± 15% (n = 10), 93 ± 13% (n = 3), 98 ± 4 (n = 3), and 89 ± 10% (n = 2), respectively.

Following 3 applications of approx imately 0.452 lb. ai/A (1.356 lbs. ai/A/season), residues of streptomyc in ranged from non-detected (ND = <0.002 ppm) to 0.478 ppm in citrus RA C whole fruit. For orange whole fruit residues ranged from ND to 0.152 ppm. For lemon whole fruit residues ranged from ND to 0.089 ppm, while residues in grapefruit whole fruit ranged from ND to 0.478 ppm.

Streptomycin residues in whole fruit without peel (flesh which represents the edible portion of citrus) ranged from ND to 0.017 ppm while residues on citrus peel ranged from ND to 1.1 22 ppm. Residues in the edible portion

of citrus fruit were much le ss than in whole fruit RAC.

Average whole fruit streptomycin re sidues in the orange decline trial ranged from 0.082 ppm at the 40-day PH I to 0.022 ppm at the 80-day PHI. For the grapefruit decline trial aver age whole fruit residues ranged from 0.043 ppm at the 40-day PHI to ND at the 80-day PHI.7 Following three applications of a pproximately 1.356 lbs. ai/A, average residues of streptomycin in processe d orange products were 0.098 ppm in the whole fruit, 0.236 ppm in the peel, 0.681 ppm in the dried pulp, and non-detectable (<0.002 ppm) in the juice and oil. These results demonstrate a concentration factor of approximately 7X in dried pulp.

B. Toxicological Profile

EPA has noted in the Streptomycin Pest icide Fact sheet (Fact Sheet Number 186, September, 1988) that streptomycin has b een used since the late 1940s to treat

bacterial infections in humans. As a result of the uses as a human drug, there is an extensive body of toxicological data available on streptomycin. Thus, all toxicological data requireme nts have been waived.

Further, it was noted in the Strept omycin TRED, June, 2006 (EPA 738-R-06-012) that EPA has evaluated the aggregate risk s from the supported registered uses and

has determined that there is a reasonable certainty that no harm to any population subgroup will result from exposure to streptomycin. In regard to the cumulative risk of streptomycin, EPA stated th e following in the Streptomycin TRED- “Unlike other pesticides for which EPA ha s followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to stre ptomycin and any other substances, and streptomycin does not appear to produce a toxic metabolite that is also produced by other substances. Therefore, EPA has not assumed that streptomycin has a common mechanism of toxicity with other substances.”

The following is relevant available toxi cological information on streptomycin:

1. Acute toxicity. No acute toxicity was identifie d in any of the relevant studies in the streptomycin database. There ar e extensive human data on streptomycin from human drug use for the last 70 years.

2. Genotoxicty. Streptomycin sulfate exhibited negative to weakly positive results in a series of genetic toxicity tests to determine its potential to interact with DNA or damage chromosomes-indica ting that it is unlikely to cause

cancer.

3. Reproductive and developmental toxicity. The European Agency for the Evaluation of Medicinal Products, Vete rinary Medicines and Information Technology (EMEA/MRL/728/00-Final, Ap ril, 2000) stated the following relative to potential reproductive effects: Panels of literature reviews and field data about the effects of streptomycin (and dihydrostreptomycin) on reproduction of farm animals were pr ovided. No adverse effects on reproduction have been reported. Stre ptomycin (and dihydrostreptomycin) did not affect the sperm quality, the fertili ty and the reproductive performances8 and induced no toxic effects on the developm ent of offsprings. From this study it was possible to conclude that the c onsumption of residues of streptomycin (and dihydrostreptomycin) in food derived from animals treated in accordance with good practice in th e use of veterinary drugs pres ents essentially no risk to peri and postnatal human health. In a teratology study rabbits were dosed at 5 and 10 mg/kg/day. No tera togenic effects were noted in this developmental study at the highest dose whic h was considered the NOAEL.

4. Subchronic toxicity. A three month feeding study in cats was conducted at doses ranging from 25-250 mg/kg/day via intramuscular injections, which is greater than the dose when used as a drug in humans or animals. Another group of cats received oral doses of 40 mg/kg/day. Ca ts which were injected lost the righting reflex, but cats whic h were dosed orally did not. Gross pathology and histopathology were unr emarkable. The NOAEL was 40 mg/kg/day. In a 3-month feeding study in guinea pigs at 40 mg/kg/day it was noted there was no hearing loss. No other remarkable findings were noted.

5. Chronic toxicity. In a 2-year feeding study rats were dosed at 0, 1, 5 and 10 mg/kg/day. The only adverse effect not ed was reduced body weight gain in male rats at 10 mg/kg/day. An increase in treatment-related tumors was not reported. The NOAEL for this study was 5 mg/kg/day. No evidence of carcinogenicity was found in a literature search of toxicity in animals or

humans.

6. Animal metabolism. The Agency has determined, and stated in the EPA Streptomycin Pesticide Fact Sheet (S eptember, 1988) that animal metabolism

data were not needed because metabolism of streptomycin in mammals has already been traced in connec tion with its use in humans.

7. Metabolite toxicology

. Streptomycin sulfate dissociates in water to streptomycin, but otherwise undergoes minimal metabolism in the environment, as well as in crops, animals and humans. The nature of the residue in plants and animals is adequa tely understood; the residue of concern is streptomycin for plant and livestock commodities and water. Due to the wide use of streptomycin as a huma n drug, and to the low residue levels expected in/on raw agricultural commodities (RACs), no metabolism data have been required.

8. Endocrine disruption

. No specific information available. No cited evidence in existing toxicological studies.

C. Aggregate Exposure

1. Dietary exposure.9 i. Food and Drinking water. EPA did a dietary and drinking water

assessment using the Dietary Exposure Evaluation Model (DEEMFCID 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) for aerial application to apples. The chronic estimated drinking water concentrations in surface and ground waters we re 0.0514 ppm and 0.0012 ppm, respectively. The dietary assessme nt for the proposed new uses on citrus used the (higher) surface wa ter concentration in water from treatment of apples in the DEEM model. The acute drinking water

concentration was not considered as streptomycin has no acute toxicological endpoint fo r risk assessment.

A new dietary+drinking water asse ssment was done with DEEMFCID version 4.02, current residue tolerances in other crops, and

citrus residue data from recent ci trus field studies with FireWall 50 WP applied by air-blast sprayers in 3 applications at ~20 day intervals. The targeted a pplication rate was 0.452 Lbs. streptomycin sulfate/acre in each application, with a 60-day

interval between the last application and harvest.

Information on residue concentrat ions in the whole fruit raw agricultural commodity (RAC), edible portion, peel, orange juice and orange oil was provided by AgroSource. No residues (LOQ=0.01 ppm) were found in orange juice or oil in crop residue

trials.

Based on evaluation of residu es in the raw agricultural

commodities with the OECD Maximum Residue Level (MRL)

calculator and other residue data provided by AgroSource, the following residue values were used for citrus:

 RAC: MRL and proposed tolerance of 0.5 ppm.

 Peel: MRL of 1.5 ppm (no tole rance required), miniscule contributor to exposure.

 Juice: Orange juice at <L OQ of 0.01 ppm. 50% convention = 0.005 ppm.

 Oil: Orange oil at <LOQ of 0.01 ppm. 50% convention = 0.005 ppm. Note that there are no hu man consumption records in the

DEEM.

 Dried pulp: 3.5 ppm. Note that there are no human consumption

records in the DEEM.

Other parameters in the modeling included:

 Existing residue tolerances for other crop uses.10  Standard DEEM processing fact ors, where appropriate, for

other commodities.

 Assumption of 100 percent crop treated for all commodities, including citrus.

 The EPA high surface drinking water estimate of 51.4 ppb (0.0514 ppm) for apple watersheds in the Streptomycin TRED,

June 2006. The surface water input was not adjusted for percent crop area treated.

 In addition, FDA has established tolerances for residues of streptomycin in uncooked, edible tissues of chickens, swine, and calves of 2.0 ppm in kidney and 0.5 ppm in other tissues as

listed in 21CFR Part 556.610. Ac cordingly, streptomycin

residues in animals were also c onsidered for inclusion in this assessment. However, 2002 USDA Food Safety and Inspection Service (USDA FSIS) National Residue Data reported no streptomycin residues in/on all livestock animals tested (2 to 634 animals in each production class). Therefore, EPA considered livestock commodities to have zero residues of streptomycin . A spot-check of the 2012 report was confirmatory in that scheduled sampling found a low frequency of residues primarily in Bob veal (typically used for pet food).

Consequently, potential residues in animal products were not considered. As noted, acute expos ure is not of concern. The EPA chronic toxicity endpoint of 5.0 mg/kg BW and uncertainty factor of 100 were used (reference dose, RfD = 0.05 mg/kg BW).

Aggregated dietary and drinking water exposures were greatest in non-nursing infants, occupyi ng 17.3 % of the chronic RfD with a margin of exposure of 578. Based on this screening level assessment of adding citrus uses, the EPA should have no

concerns about excess risk.

2. Non-dietary exposure . EPA noted the following in the “ Report of the Food Quality Protection Act (FQPA) Tole rance Reassessment Progress and Risk Management Decision (TRED) for Streptomycin ”; EPA 738-R-06-012; June, 2006, with regard to reside ntial risk: “At this time, products containing streptomycin are registered for resi dential use on home garden orchards (apples and pears), and ornamentals (pyracantha, chrysanthemums, dieffenbachia, philodendron and roses). Dermal and inhalation exposure to residential handlers can occur when they mix, load, or apply streptomycin for use in a sprayer.”

Oral absorption of chemicals related to streptomycin is less than 1% because of the charged nature of the molecules. Because the skin has a protective11 barrier role in comparison to the lining of the gastrointestinal tract, dermal absorption is expected to be much less th an that by the oral route. Although a dermal exposure study is not available fo r streptomycin, dermal absorption at

environmental concentrations is expected to be so mi nimal that toxicity by the

dermal route is not of concern. Ther efore, quantificati on of risk following dermal exposure is not required at this time.

A chronic inhalation exposure asse ssment was conducted for homeowner application to fruit trees and shrubs using a low-pressure hand wand. EPA

calculated the residential inhalati on exposure of 0.000067 mg/kg/day. The resulting margin of exposure (MOE) is 75,000. MOEs (calculated as NOAEL ÷ dose) greater than 100, do not exceed EPA’s level of concern; because the MOE for this use is greater than 100, ri sk from residential inhalation exposure does not exceed EPA’s level of concern. The inhalation exposure assessment

is considered a reasonable worst-ca se scenario for homeowners because streptomycin is poorly absorbed by the or al and dermal routes; therefore, a post application dermal and oral expos ure assessment was not conducted.”

The proposed new uses on citrus have no impact on the EPA’s previous assessments of residential exposur es and findings of no concern.

D. Cumulative Effects

EPA has stated the following in the St reptomycin TRED (EPA 738-R-06-012, June, 2006): Unlike other pesticides for which EPA ha s followed a cumulative risk approach

based on a common mechanism of toxicit y, EPA has not made a common mechanism of toxicity finding as to streptomycin and any other substances, and streptomycin does not appear to produce a toxic metabolite th at is also produced by other substances. Therefore, EPA has not assumed that st reptomycin has a common mechanism of toxicity with ot her substances.

E. Safety Determination

1. U.S. population. In the Streptomycin TRED, EPA aggregated residential inhalation exposure and chr onic dietary exposure. The same procedure has been used for this safety determination. Accordingly, the sum of chronic dietary exposure for the U.S. populati on (0.002265 mg/kg/day) plus residential (garden) exposure (0.000067 mg/kg/day) are a total of 0.0023 mg/kg/day (MOE 2,140). When compared to a hu man therapeutic dose of 15 mg/kg/day, the above noted dietary (plus residen tial) exposures would have minimal impact and cause no harm.

2. Infants and children

. Aggregate residential inhalation exposure (0.000067 mg/kg/day) plus non-nursing infant s (0.008457 mg/kg/day) totaling 0.0085 mg/kg/day is well below the human ther apeutic dose of 15 mg/kg/day, again demonstrating the dietary (plus reside ntial) exposures would have minimal12 impact and cause no harm.

F. International Tolerances

No available information.