Interregional Research Project No. 4 (IR

- 4)

Pesticide Petition #4E8236 EPA has received a pesticide petition ( 4E8236 ) from Interregional Research Project No. 4 (IR

- 4), Rutgers, the State Universit y of New Jersey, 500 College Road East, Suite 201W, Princeton, NJ 08540 request ing, 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 .245 by 1) establishing tolerances for residues of the fungicide streptomy cin in or on grapefruit; grapefruit, dried pulp; fruit, pome, group 11

- 10 ; 2) moving the existing tolerances for streptom yc in on celery , pepper, and tomato from paragraph (a)(2), and potato from paragraph (a)(3) to the table in (a)(1) ; 3) modif yi ng the existing tolerance for tomat o from 0.25 ppm to 0.5 ppm ; 4) removing the existing time limited tolerances for grapefruit and grapefruit, dried pulp in paragraph (b) upon establishment of the permanent tolerances for grape fruit and grapefruit, dried pulp; 5 ) remov ing the existing tol erance for fruit, pome, group 11 upon establishment of the tolerance for fruit, pome, group 11
- 10 ; and 6) modifying the tolerance expression and creating a single paragraph and table under 180.245 (a) to read as follows: (a) General. Tolerances are establ ished for residues of the fungicide streptomycin, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only streptom ycin (O

- 2
- Deox y - 2
- (m eth yl amino)

- a - L
- glucop yr anos yl

- (1

- 2)

- O
- 5
- deoxy

- 3
- C
- formyl

- a - L
- ly

xofuranosyl

- (1

- 4)

- N,N’
- bis(aminoiminomethyl)

- D
- streptamine) in or on the commodity

. EPA has determined that the petition contains data or information regarding the elements set forth in secti on 408 (d) (2) of FFDCA; however, EPA has not full y 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. 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:  Metabolism of streptomycin in mammals has already b een traced in connection with its use in humans;  Residues are non

- detectable (<0.5 p pm ) in or on crops when treated according to label use rates and directions;  Large amounts of toxicological data exist;  Most crops are treated at or before transplanting (c elery , peppers, potatoes, tomatoes) and po me fruits are treated fo liarl y but with a 30

- day PHI for pears and a 50
- day PHI for apples and crabapples;  Potential daily

exposure to streptomycin as a pesticide is <0.01% of the daily clinical dosage (1

- 4 grams/day).2

2. Analytical method. Grapefruit and tomato s amples were anal yz ed for streptomycin using a laboratory working method based on USDA Food Safety and Inspection Service SOP No: CL G
- AMG1.02, “Confirmation of Aminogl ycosides by HPL C
- MS/MS”. Modif

ications were made to improve the performance of the method for the various crop fractions. Briefl y, residues were extracted b y homogenizing and shaking with phosphate buffer. (The grapefruit (citrus) oil did not require homogenization ) . The tomato paste did not require shaking ). After filtration (RAC and juice) or centrifugation (oil and dried pulp, and tomato fractions) , the extracts were subjected to C8 SPE cleanup. The pH of the eluate from the C8 column was adjusted and loaded onto a CBX SPE column for further purification. The anal yt e was eluted from the column with acidic methanol solution. The methanolic extracts were then evaporated and reconstituted in water. The reconstituted residues were anal yz ed b y ion

- pair reversed

- phase liquid chromato graph y with detection by

MS/MS spectrometry

. Based on recoveries of grapefruit fraction samples fortified at the LLMV, the limit of detection (L OD) and limit of quantitation (LOQ) were calculated as 0.0038 ppm and 0.011 ppm, respectively , for RAC, as 0.0 045 ppm and 0.013 ppm, respectivel y, for oil, as 0.0044 ppm and 0.013 ppm, respectivel y for juice, and as 0.0037 ppm and 0.011 ppm, respectivel y, for dried pulp. For tomato fractions , the limit of detection (LOD) and limit of quantitation (LOQ) were calcu lated as 0.0020 ppm and 0.0061 ppm, respectivel y, for RAC, as 0.0047 ppm and 0.014 ppm, respectively , for puree, and as 0.0042 ppm and 0.012 ppm respectivel y for paste. Treated grapefruit samples were anal yz ed within 13 day s of extraction (one dried pulp extract was anal yz ed after 25 day s). Treated tomato samples were analyzed within 10 day s of extraction. Analy tical sets ty

pically consisted of calibration standards, unfortified controls, fortified controls, and treated samples. The anal yt ical standard solutions were stored refrigerated (approximately

- 0.2 to 11  C).

3. Magnitude of residues. Tomato : Nineteen tomato trials w ere conducted during the 2009 growing season. Three different ty

pes of tomatoes were grown for this study , processing varieties (field), fresh market varieties (field and greenhouse), and < 1

- inch varieties (field and greenhouse). Processing varieties we re grown in six field trials covering the states of NY , CA (three locations), NM and AZ; fresh market varieties were grown in seven field trials covering the states of WI , FL, CA (four locations) and NM and two greenhouse trials in the states of CA and FL; and < 1

- inch varieties were grown in two field trials in the states of NC and CA and two greenhouse trials in the states of MD and CO. The number of trials and their locations are in accordance with OPPTS Guideline 860.1500 for the EPA regions represente d by the trials. In each trial, the test substance was applied four times as a foliar spray to runoff (or near runoff) at concentrations of approximately 203.73 ppm at up to 125 GPA per application. The delivery rate varied based on the size of the plants at the time of3

application (ranging from 65.08 to 137.10 GPA); delivery rates of up to 125 GPA + 10% were considered within the protocol limits. All tank mixes included an adjuvant, except for the first application in one of the CA locations (fresh market, field), where it was omitted due to an oversight. The applications were made 6 to 8 day s apart and timed so that marketable tomatoes could be collected 1 day

after the final application. Additional samples were collected for decline determination f

rom two separate CA sites, one fresh market, field and one fresh market, greenhouse at approximately 3, 7, 14, and 21 day s. In addition, bulk samples were collected from the NY site for processing into puree and paste. The maximum storage interval for treated tomato samples in this study was 332 day s for tomato raw agricultural commodity (RAC), 394 day s for puree, and 401 day s for paste. Storage stability testing was performed after 336 day s (RAC), 415 day s (puree), and 436 day s (puree) of storage. Results demonstrated stability

. The nature of the residues of streptomy cin is adequately understood and an acceptable analy

tical method is available for enforcement purposes. The lowest level of method validation (LLMV) was 0.01 ppm. The results from the trials show that the maximum residues following four applications at concentrations of approximately 203.73 ppm at up to 125 GPA (+ 10%) and a pre

- harvest interval ( PHI) of 1 day were 0.413 ppm. Residues declined over time. Residues of streptomy cin did not concentrate in the processe d fractions of puree and paste. These results (i.e., residues less than 0.5 ppm) are consistent with the points noted in the Metabolis m discussion under Number 1 above. Grapefruit : E ight field trials were conducted in Florida ( EPA region 3 ), Texas (region 6), and California (region 10) during the 2008 growing season. The number of field trials and their locations are in accordance with OPPTS Guideline 860.1500. The product used in this study , Firewall 17WP, contains 22.4% of streptomycin sulfate, which is equivalent to 17% of streptomycin. Calculations of the application rates in this study

were based on the amount of the application of 2 lbs of Firewall 17WP. Streptomycin sulfate (22.4%) was used to calculate the rate of active ingredient in the protocol. The amount of active ingredient, as expressed on the label, should be based on the streptomycin (17%) content. This was documented with a deviation. In each trial, the test substance was applied in two foliar applications of approxim ately

2.0 lbs product per acre, for a total of approximately 4.0 lbs product per acre. In one FL trial , the test substance was applied to an additional plot at 5X the application rate to provide grapefruit for processing into oil, juice, and dried pulp. Inthis additional plot, two applications of approximately 10.0 lbs product per acre each were made, for a total of approximately 20.0 lbs product per acre. Crop oil was included in each tank mix except those used for the first application in two FL locat ions

. All applications were made at 20

- to 22
- day intervals and timed so that marketable grapefruit could be collected approximately 60 day s after the final application. Additional samples for decline determination were collected from a TX location at 0, 7, 14, 20, and 41 day s.4 Sample anal ys is for residues of streptom ycin was conducted b y the Food and Environmental Toxicology L aboratory , Gainesville, FL. The maximum storage interval for field

- treated samples in this study was 356 days for grapefruit raw agricultural commodity

(RAC), 471 day s for oil (approximately 15 months), 453 day s for juice, and 640 day s (approximately

21 months) for dried pulp. Storage stability testin g was performed after 327 day s (RAC), 474 and 502 days (oil), 481 day s (juice), and 720 day s (dried pulp) of storage. With the exception of oil, results demonstrated stability . At 474 day s, oil samples yielded recoveries of approximately 25 to 40%; when analy

zed at 502 day s, recoveries were approximately 30%. The nature of the residues of streptomy cin is adequately understood and an acceptable analy

tical method is available for enforcement purposes. The lowest level of method validation (LLMV) was 0.01 ppm for RAC, oil, and juice, and 0.02 ppm for dried pulp. The results from the trials show that s treptomycin residues ranged from < 0.01 to 0.0855 ppm in 60

- day

RAC samples following a total applicat ion of approximately 4.0 lbs product per acre

. Residues declined over time , from a maximum of 0.136 ppm at 0 day s to a maximum of 0.0479 ppm at 57 day s. For the processed fractions generated from grapefruit treated at 5X, residues were 0.698 ppm in dried pulp and < 0.01 ppm in both oil and juice. A comparison of the residues in the RAC with those in each processed fraction resulted in concentrated residues in pulp by a factor of 4.2 X and reduced residues in oil and juice by

a factor of 0.06 X each. B. Toxicological Profile EPA has noted in the Streptomycin Pesticide Fact sheet (Fact Sheet Number 186, September, 1988) that streptomycin has been used since the late 1940’s to treat bacterial infections in humans. As a result of th e uses as a human drug , there is an extensive body of toxicological data available on streptom ycin. Thu s, all toxicological data requirements have been waived. Further, it was noted in the Streptomycin TRED, June, 2006 (EPA 738

- R
- 06
- 012) that EPA has evaluated the aggregate risks 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 the following i n the Streptomycin 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 streptomy cin and any other substances, and strepto mycin does not appear to produce a toxic metabolite that is also produced by other substances. Therefore, EPA has not assumed that streptomy cin has a common mechanism of toxicity

with other substances. The following is relevant available toxicological in formation on streptomycin. 1. Acute toxicity. The acute toxicity of the FireWall 17 WP formulation of streptomycin sulfate is summarized in the following table:5

2. Genotoxicty. Streptomycin sulfate exhibited negative to weakl y positive results in a series of genetic toxicity t ests to determine its potential to interact with DNA or damage chromosomes

- indicating that it is unlikely t o cause cancer. 3. Reproductive and dev elopmental toxicity. The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines and Information Technology

(EMEA/MRL/728/00

- Final, April, 2000) stated the following relative to potent ial reproductive effects: Panels of literature reviews and field data about the effects of streptomy cin (and dihydrostreptomy cin) on reproduction of farm animals were provided. No adverse effects on reproduction have been reported. Streptom ycin (and dihydro streptomycin) did not affect the sperm quality , the fertility and the reproductive performances and induced no toxic effects on the development of offsprings. From this study

it was possible to conclude that the consumption of residues of streptomycin (an d dihydrostreptomy cin) in food derived from animals treated in accordance with good practice in the use of veterinary drugs presents essentiall y no risk to peri and post natal human health. In a teratology

study rabbits were dosed at 5 and 10 mg/kg/day

. No teratogenic effects were noted in this developmental study at the highest dose which 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. Cats which were injected lost the righting reflex, but cats which were dosed orally did not. Gross pathology and histopathology

were unremarkable. The NOAEL was 40 mg/kg/day . In a 3
- month feeding stud y 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. Ina 2
- ye ar feeding stud y rats were d osed at 0, 1, 5 and 10 **Route of application Animal**  **FireWall 17 WP formulated product**  Oral L D 50 Rat >5 ,000 mg/kg Dermal L D 50 Rat >5 ,000 mg/kg Inhalation L C 50 Rat >2.09 mg/L air

– 4 hours Skin irritation Rabbit Slightly irritating Ey e irritation Rabbit Mildly irritating Skin sensitization Guinea pig No evidence of sensitization observed6 mg/kg/day . The onl y adverse effect noted was reduced bod y 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 (September, 1988) that animal metabolism data were not needed because m etabolism of streptomy cin in mammals has alread y been traced in connection 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 cro ps, animals and humans. The nature of the residue in plants and animals is adequatel y understood; the residue of concern is streptomycin for plant and livestock commodities and water. Due to the wide use of streptom ycin as a human 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. i. Food and ii. Drinking water
. EPA did a dietary and drinking water assessment 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 evaluatio n 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 were 0.0514 ppm and 0.0012 ppm, respectivel y. The dietary assessment for the proposed new uses on grapefruit and tomatoes used the (higher) surface water 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 for risk assessment. N o residues (LOQ=0.01 ppm) were found in juice or oil in crop residue tri als. IR
- 4 evaluated grapefruit and tomato residues with the NAFTA Maximum Residue Level (MRL) Excel spreadsheet and has proposed the NAFTA MRLs (g rapefruit: 0.15 ppm and Tomatoes: 0.50 ppm ) as tolerances

. D ietary and drinking water exposure and risk asse ssments we re done with DEEM

- FCID Version 3 .16 03
- 08
- d based on the NHANES 2003

- 2008 food consumption survey . The commodities grapefruit and grapefruit juice were added to the residue file in the latest EPA chronic dietary assessment ( DP No. D310391,7 1/9/0 6 ) with the high FIRST surface water concentration with the following additional inputs : 0.15 ppm in grapefruit , 0.005 ppm (50% LOQ) in grapefruit juice , 0.50 ppm in tomatoes, d efault processing factor s (except for grapefruit juice and the assumption that 100% of crop treated. Itshould be noted that EPA has determined that animal products are not of concern and need not be quantitatively

evaluated. While citrus pulp may be a minor component of cattle feed, it is not included in the Maximum Reasonable Bal anced Diet and should not be of concern. Itshould be noted that the cited residue file contained estimates of percent crop treated for apples and pears of 10% and 25%, respectively . However, the text noted PCTs of 20% and 30% respectivel y. For this die tary risk assessment the conservative (20 and 30%) estimates were used

. As previously noted, acute exposure is not of concern. The EPA chronic toxicity endpoint of 5.0 mg/kg BW and uncertainty factor of 100 were used (refe rence dose, RfD, 0.05 mg/kg BW). Aggregated dietary

and drinking water exposures were greatest in non

- nursing infants, occup yi ng 10.6 % of the chronic RfD with a margin of exposure of 945 . Based on this screening level assessment of adding grapefruit uses and increasing tomato tolerances, 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) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Streptomycin ”; E PA 738
- R
- 06
- 012; June, 2006, with regard to residential risk: “ At this time, products containing streptomycin are registered for residential use on home garden orchards (apples and pears), and ornamentals (py racantha, chry santhemums, dieffenbachia, philode ndron and roses). Dermal and inhalation exposure to residential handlers can occur when they mix, load, or apply

streptomycin for use in a spray er. Oral absorption of chemicals related to streptomycin is less than 1% because of the charged nature of the molecules. Because the skin has a protective barrier role in comparison to the lining of the gastrointestinal tract, dermal absorption is expected to be much less than that b y the oral route. Although a dermal exposure study

is not available for streptom ycin, dermal absorption at environmental concentrations is expected to be so minimal that toxicity by the dermal route is not of concern. Therefore, quantification of risk following dermal exposure is not required at this time. A chronic inhalation exposure assessment was conducted for homeowner application to fruit trees and shrubs using a low pressure handwand. 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, risk from residential inhalation exposure8 does not exceed EPA’s level of concern. The inhalation exposure assessment is considered a reasonabl e worst - case scenario for homeowners because streptomycin is poorl y absorbed b y the oral and dermal routes; therefore, a postapplication dermal and oral exposure assessment was not conducted.” The proposed new uses on grapefruit and tomatoes have no impac t on the EPA’s previous assessments of residential exposures and findings of no concern. D. Cumulative Effects EPA has stated the following in the Streptom ycin TRED (EPA 738

- R
- 06
- 012, June, 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 streptom ycin and an y other substances, and streptomycin does not appear to produce a toxic metabolite that is also produced b y other substances. Therefore, EPA has not assumed that streptomy cin has a common mechanism of toxicity

with other substances. E. Safety Determination 1. U.S. population. Inthe Streptomycin TRED , EPA aggregated residential inhalation exposure and chronic dietary exposure. The same procedure has been used for this safety

determination. Accordingl y, the sum of chronic dietary exposure f

or the U.S. population (0.002300 mg/kg/day) plus residential ( garden) exposure (0.000067 mg/kg/day) are a total of 0.002367 mg/kg/day (MOE 2,112)

. When compared to a human therapeutic dose of 15 mg/kg/day , the above noted dietary (plus residential) 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 infants (0.005292 mg/kg/day) totaling 0.005359 mg/kg/day is well below the human therapeutic dose of 15 mg/kg/day , again demonstrating the dietary (plus residenti al) exposures would have minimal impact and cause no harm. F. International Tolerances No available information.