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Kasugamycin Crops Identification of Petitioned Substance United States Department of Agriculture Agricultural Marketing Service | National Organic Program Document Cover Sheet https://www.ams.usda.gov/rules-regulations/organic/national-list/petitioned Document Type: ☐ National List Petition or Petition Update A petition is a request to amend the USDA National Organic Program’s National List of Allowed and Prohibited Substances (National List). Any person may submit a petition to have a substance evaluated by the National Organic Standards Board (7 CFR 205.607(a)). Guidelines for submitting a petition are available in the NOP Handbook as NOP 3011, National List Petition Guidelines. Petitions are posted for the public on the NOP website for Petitioned Substances. ☒ Technical Report A technical report is developed in response to a petition to amend the National List. Reports are also developed to assist in the review of substances that are already on the National List. Technical reports are completed by third-party contractors and are available to the public on the NOP website for Petitioned Substances. Contractor names and dates completed are available in the report. Kasugamycin Crops Identification of Petitioned Substance 1 Chemical Names: Other Name: 2 Kasugamycin Kasugamycin hydrochloride hydrate 3 2-amino-2-[(2R,3S,5S,6R)-5-amino-2-methyl-6- Kasugamycin monohydrochloride 4 [(2R,3S,5S,6S)-2,3,4,5,6- 5 pentahydroxycyclohexyl]oxyoxan-3- Trade Names: 6 yl]iminoacetic acid (IUPAC name) Kasumin 2L, Kasumin 4L 7 8 3-O-[2-amino-4-[(carboxyiminomethyl)amino]- CAS Numbers: 9 2,3,4,6-tetradeoxy-a-D-arabino-hexopyranosyl]- Kasugamycin (6980-18-3) 10 D-chiro-inositol Kasugamycin monohydrochloride (19408-46-9) 11 12 Other Codes: 13 Kasugamycin Pub Chem CID 65174 14 15 16 Summary of Petitioned Use 17 18 The National Organic Program (NOP) was petitioned to add kasugamycin as an allowed synthetic to the 19 synthetic substances National List at 7 CFR §205.601. Alternate formulated names are kasugamycin 20 monohydrochloride and kasugamycin hydrochloride hydrate. The specific petitioned use is for control of 21 fire blight caused by Erwinia amylovora in apples, pears, and other pome fruits (California Apple 22 Commission 2020). 23 24 25 26 Characterization of Petitioned Substance 27 28 Composition of the Substance: 29 Kasugamycin is an aminoglycoside containing the sugar inositol. Kasugamycin hydrochloride is isolated 30 during the manufacture of kasugamycin. Kasugamycin hydrochloride hydrate is the registered active 31 ingredient in the Kasumin brand formulations. The structure of kasugamycin hydrochloride hydrate is 32 shown in Figure 1 (U.S. EPA 2005). The inositol moiety is on the right-hand side of the illustration. 33 ___________________________________ January 20, 2021 Technical Evaluation Report Page 1 of 31 Compiled by Nexight Group for the USDA National Organic Program Technical Evaluation Report Kasugamycin Crops 34 Figure 1. Structure of Kasugamycin Hydrochloride Hydrate 35 36 Source or Origin of the Substance: 37 Kasugamycin is obtained by aerobic fermentation of the microorganism Streptomyces kasugaensis. This 38 microorganism was originally discovered near the Kasuga Grand Shrine in Nara City, Japan. The active 39 ingredient kasugamycin hydrochloride hydrate is isolated from kasugamycin fermentation product 40 (Umezawa et al. 1967). 41 42 Properties of the Substance: 43 Kasugamycin is a colorless solid at room temperature and normal atmospheric pressure. The free base 44 melts with decomposition at 214–216°C. The molecular formula is C14H25N3O9 and the molecular weight is 45 379.36 g/mol (U.S. EPA 2005; PubChem 2020a). 46 47 Kasugamycin hydrochloride is composed of white crystals that melt with decomposition at 236–239°C. The 48 molecular formula is C14H26ClN3O9 and the molecular weight is 415.82 g/mol. The hydrochloride hydrate 49 has a molecular weight of 433.8 g/mol. The bulk density of the hydrochloride hydrate is 0.43 g/ml at 50 24.5°C. 51 52 The hydrochloride is soluble in water with a maximum solubility of about 228 g/liter at pH 7. It is more 53 soluble in alkaline solutions. The Environmental Protection Agency (EPA) reports 207 g/liter at pH 5, 54 228 g/liter at pH 7, and 438 g/liter at pH 11 (U.S. EPA 2005). Kasugamycin hydrochloride hydrate is the 55 active ingredient in the Kasumin formulations (U.S. EPA 2018). 56 57 Kasugamycin hydrochloride hydrate is insoluble in ethanol, acetone, ethyl acetate, chloroform, and 58 benzene and sparingly soluble in methanol. It has three ionizable groups, carboxyl group, cyclic primary 59 amine, and secondary amine, with pKa values of pKa1 = 3.23, pKa2 = 7.73 and pKa3 = 11.0. The pKa1 60 refers to ionization of a carboxyl group. The pKa2 measures ionization of the cyclic primary amine. The 61 pKa3 measures ionization of the secondary amine (U.S. EPA 2005). 62 63 When the hydrochloride is dissolved in water, the carboxyl group ionizes, making the solution acidic. 64 Aqueous solutions (1 percent wt/vol) of the hydrochloride are acidic with a pH of 4.35 at 24.5°C. It is much 65 more soluble in alkaline solutions. Raising the pH from 5 (207 g/liter) to 9 (438 g/liter) more than doubles 66 solubility (U.S. EPA 2005). More alkaline solutions, however, tend to be unstable, and undergo slow 67 decomposition. See Evaluation Question #4 for more information. 68 69 Kasugamycin hydrochloride has relatively low volatility with a vapor pressure of <0.013 mPa at 25°C 70 (about 0.13 atmospheres). Dried residues of the hydrochloride do not volatilize readily from soil into air. 71 The hydrochloride is about 100 times more soluble in water than octanol with log Kow (i.e., the January 20, 2021 Page 2 of 31 Technical Evaluation Report Kasugamycin Crops 72 concentration of the test substance in octanol divided by the concentration in water) = -1.96. PubChem 73 (2020b) provides an estimate of log Kow = -5.75. The higher solubility of the hydrochloride in water versus 74 octanol means that there is little tendency for bioaccumulation in aquatic organisms. See Evaluation 75 Question #6 for more information. 76 77 In water between pH 5–9, kasugamycin hydrochloride solutions form a zwitterion. This means the 78 carboxylic group is mostly ionized, and the proton is captured by the primary amine. This salt-like ion is 79 not very volatile, and kasugamycin does not volatilize readily from water (U.S. EPA 2013). See Evaluation 80 Question #4 for more information. 81 82 Specific Uses of the Substance: 83 The specific use described in the petition is for the control of fire blight caused by Erwinia amylovora in 84 apples, pears, and other pome fruits. In a small-scale trial with Bartlett pears, kasugamycin at 100 ppm 85 applied 18 hours after inoculation with Erwinia reduced disease incidence by more than 66 percent 86 (Adaskaveg et al. 2009). 87 88 In commercial California pear orchards from 2006–2010, kasugamycin applied three to six times at 100 ppm 89 during bloom led to a 77–78 percent reduction of fire blight disease incidence in fields deliberately 90 inoculated with Erwinia. In fields not inoculated with Erwinia, there was an 80–90 percent reduction in 91 disease incidence. Kasugamycin was more effective than oxytetracycline, and it worked equally well on 92 isolates either resistant or not resistant to streptomycin. More than four applications led to phytotoxicity 93 (Adaskaveg et al. 2009; Adaskaveg et al. 2011). 94 95 In Erwinia-inoculated Bartlett pear and Golden Delicious apple orchards in Oregon, two applications of 96 kasugamycin at 100 ppm reduced disease incidence 93 percent in pears and 77 percent in apples (Johnson 97 et al. 2008). In the most favorable case among Jonathan or Gala apples in New York orchards, 100 ppm 98 kasugamycin was applied the day before and the day after inoculation with Erwinia. Disease control after 99 application was 91 percent (Sundin 2014). 100 101 Kasugamycin has also been used to control other plant diseases that are described in Historic Use. 102 103 Approved Legal Uses of the Substance: 104 The U.S. EPA has registered Kasumin 2L and Kasumin 4L for control of plant diseases, especially fire blight 105 caused by Erwinia amylovora on apples and pears. These are formulations containing the active ingredient 106 kasugamycin hydrochloride hydrate (U.S. EPA 2018; U.S. EPA 2020). 107 108 Action of the Substance: 109 Kasugamycin is an antibiotic that inhibits bacterial protein synthesis. This process is discussed further in 110 Evaluation Question #5. 111 112 Combinations of the Substance: 113 Kasugamycin is not a precursor to, a component of, nor used in combination with another substance on the 114 National List. Currently registered formulations are Kasumin 2L and Kasumin 4L, which are not compliant 115 with NOP requirements for organic production. These contain surfactants and the preservative 1,2- 116 benzisothiazolone which are not allowed as inerts under 7 §CFR 205.601(m) (Kasumin SDS 2015; U.S. EPA 117 2018; U.S. EPA 2020;). The petitioner states that the manufacturer is willing to develop a formulation that is 118 compliant for organic use if kasugamycin is approved (California Apple Commission 2020). 119 120 121 Status 122 123 Historic Use: 124 The Japanese scientist Hamao Umezawa and his colleagues produced kasugamycin by aerobic 125 fermentation of Streptomyces kasugaensis in 1965 (Umezawa et al. 1965; Umezawa et al. 1967). Production 126 with a different organism, Streptomyces kasugaspinus, was patented later (Umezawa et al. 1971). January 20, 2021 Page 3 of 31 Technical Evaluation Report Kasugamycin Crops 127 128 Tamamura and Sato (1999) found “that kasugamycin possesses weak or almost no antibacterial activity 129 against common pathogenic bacteria in human or animals.” According to Levitan (1967), “kasugamycin 130 was noted to be more effective against Pseudomonas species than against some of the other bacteria tested, 131 results were nevertheless uniformly disappointing” (753).
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