PUBLICLY RELEASABLE SUMMARY OF THE PETITION 

FOR ESTABLISHMENT OF A TOLERANCE 

FOR RESIDUES OF STREPTOMYCIN 

IN OR ON AGRICULTURAL COMMODITIES, 

CITRUS FRUITS, GROUP 10 -10 

 
2 

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. 

Pesticide Petition Number 5F8427

EPA has received a pesticide petition (PP# 5F8427) 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 streptomycin in or on the raw 

agricultural commodities citrus fruit, Crop Group 10-10, at 0.5 ppm, and citrus, dried 

pulp at 3.5 ppm. Geo Logic Corp. proposes 1) the modifications of the tolerance 

expression for streptomycin in paragraphs (a)(1), (a)(2) and (a)(3) in 40 CFR 180.245 

as shown below and proposes 2) the removal of the time limited tolerances for 

grapefruit and grapefruit dried pulp in paragraph 3(b) of 40 CFR 180.245 upon approval 

of the requested tolerances for citrus and citrus dried pulp. 

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

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 streptomycin (O-2-Deoxy-2-(methylamino)-a-Lglucopyranosyl-(1-2)-O-5-deoxy-3-C-formyl-a-L-lyxofuranosyl-(1-4)-N,N’-

bis(aminoiminomethyl)-D-streptamine) 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/bactericide streptomycin, 

including 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-glucopyranosyl-(1-2)-O-5-deoxy-3-C-formyl-aL- lyxofuranosyl-(1-4)-N,N’-bis(aminoiminomethyl)-D-streptamine) in or on the 

commodity. 
3 

(3) Tolerances are established for residues of the fungicide/bactericide streptomycin, 

including its metabolites and degradates, from treatment of seed pieces, 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-lyxofuranosyl-

(1-4)-N,N’-bis(aminoiminomethyl)-D-streptamine) 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 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 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)-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. 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: 

i. Metabolism of streptomycin in mammals 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 0.25 
4 

according to label use rates and directions; 

iii. Large amounts of toxicological data exist; 

iv. Most crops are treated at or before 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 streptomycin as a pesticide is <0.01% 

of the daily clinical dosage (1-4 grams/day). 

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

laboratory working method based on USDA Food Safety and Inspection 

Service SOP No: CLG-AMG1.02, “Confirmation 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 ppm, respectively, for streptomycin in all 

matrices except for dried pulp which 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 column 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 then evaporated and reconstituted in 

0.1% formic acid in water. The reconstituted 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 efficiency of the analytical method was 

determined at the time of analysis with each set of samples by fortifying 

subsamples of the control citrus matrix, processing them according to the 

analytical method, and analyzing them similar to a field-treated sample. 

Control matrices fortified at approximately the LOQ (0.01 ppm or 0.05 

ppm) and 10 times the LOQ (0.10 ppm or 0.50 ppm) were typically 
5 

included in the analysis set for method 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 commodities of citrus, Crop Group 10-10 

following applications of FireWall 50 WP (streptomycin sulfate). The 

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 FireWall 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 approximately 1.356 

lbs. 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 1.356 lbs. ai/A or 4.068 

lbs. ai/A/season. 

FireWall 50 WP is a broad spectrum fungicide/bactericide formulated as a 

wettable powder (WP) which nominally contained 65.8% of the active 

ingredient, streptomycin sulfate, equivalent to 50% streptomycin. 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 10-10) 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 each at a 3x rate (1.356 lbs. 

ai/A) for the purpose of producing whole fruit to be processed into the 
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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. ai/A for the 3x rate, processing treated 

plot (T2). Actual spray volumes ranged from 91 – 109 gallons per acre. 

Each treated plot received three applications sprayed at a target 21-day 

spray interval. 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, 50, 62, 70, and 80 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 214 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 streptomycin were determined 

using the analytical method, “Analytical Method for Streptomycin 

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 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 citrus whole fruit, citrus whole fruit 

without the peel, citrus peel, orange oil, 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 approximately 0.452 lb. ai/A (1.356 lbs. 

ai/A/season), residues of streptomycin ranged from non-detected (ND = 

<0.002 ppm) to 0.478 ppm in citrus RAC 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 1.122 ppm. Residues in the edible portion 

of citrus fruit were much less than in whole fruit RAC. 

Average whole fruit streptomycin residues in the orange decline trial 

ranged from 0.082 ppm at the 40-day PHI to 0.022 ppm at the 80-day PHI. 

For the grapefruit decline trial average 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 approximately 1.356 lbs. ai/A, average 

residues of streptomycin in processed 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 Pesticide Fact sheet (Fact Sheet Number 186, 

September, 1988) that streptomycin has been 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 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 in 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 streptomycin 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 toxicological information on streptomycin: 

1. Acute toxicity. No acute toxicity was identified in any of the relevant studies 

in the streptomycin database. There are 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-indicating that it is unlikely to cause 

cancer. 

3. Reproductive and developmental 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 potential reproductive effects: Panels of literature reviews and field 

data about the effects of streptomycin (and dihydrostreptomycin) on 

reproduction of farm animals were provided. No adverse effects on 

reproduction have been reported. Streptomycin (and dihydrostreptomycin) did 

not affect the sperm quality, the fertility and the reproductive performances 
8 

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 

(and dihydrostreptomycin) in food derived from animals treated in accordance 

with good practice in the use of veterinary drugs presents essentially no risk to 

peri and postnatal 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 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 noted 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 (September, 1988) that animal metabolism 

data were not needed because metabolism of streptomycin in mammals has 

already 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 crops, animals and humans. The nature of the 

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

is streptomycin for plant and livestock commodities and water. Due to the 

wide use of streptomycin 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. 
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i. Food and Drinking water. EPA did a dietary and drinking water 

assessment using the Dietary Exposure Evaluation Model (DEEMFCIDTM), 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 were 0.0514 ppm and 0.0012 ppm, 

respectively. The dietary assessment for the proposed new uses on 

citrus 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. 

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

citrus residue data from recent citrus field studies with FireWall 50 

WP applied by air-blast sprayers in 3 applications at ~20 day 

intervals. The targeted application 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 concentrations 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 residues 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 tolerance required), miniscule 

 contributor to exposure. 

 Juice: Orange juice at <LOQ 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 human 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 factors, 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. Accordingly, streptomycin 

residues in animals were also considered 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 exposure 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, occupying 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) Tolerance Reassessment Progress and Risk 

Management Decision (TRED) for Streptomycin”; EPA 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 (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 protective 
11 

barrier role in comparison to the lining of the gastrointestinal tract, dermal 

absorption is expected to be much less than that by the oral route. Although a 

dermal exposure study is not available for streptomycin, 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 hand wand. EPA 

calculated the residential inhalation 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, risk from residential inhalation exposure 

does not exceed EPA’s level of concern. The inhalation exposure assessment 

is considered a reasonable worst-case scenario for homeowners because 

streptomycin is poorly absorbed by the oral and dermal routes; therefore, a post 

application dermal and oral exposure assessment was not conducted.” 

The proposed new uses on citrus have no impact on the EPA’s previous 

assessments of residential exposures and findings of no concern. 

D. Cumulative Effects 

EPA has stated the following in the Streptomycin 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 streptomycin 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. 

E. Safety Determination

1. U.S. population. In the Streptomycin TRED, EPA aggregated residential 

inhalation exposure and chronic dietary exposure. The same procedure has 

been used for this safety determination. Accordingly, the sum of chronic 

dietary exposure for the U.S. population (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 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 (0.008457 mg/kg/day) totaling 0.0085 

mg/kg/day is well below the human therapeutic dose of 15 mg/kg/day, again 

demonstrating the dietary (plus residential) exposures would have minimal 
12 

impact and cause no harm. 

F. International Tolerances

No available information.