i

EPA BIOPESTICIDES AND POLLUTION PREVENTION DIVISION 

COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN 

THE FEDERAL REGISTER 

EPA Biopesticides and Pollution Prevention Division contact: [insert name and 

telephone number with area code] 

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green, i.e., “[insert 

company name],” with the information specific to your action.

SUBMISSION: E-mail the completed template to: hollis.linda@epa.gov.

TEMPLATE: 

[Kaken Pharmaceutical Co., Ltd.]

[Insert petition number]

 EPA has received a pesticide petition ([for an exemption from the requirement of 

a tolerance for residues of polyoxin D zinc salt in/on all agricultural commodities]) from 

[Kaken Pharmaceutical Co., Ltd.], [c/o Conn & Smith, Inc., Agent, 6713 Catskill Road, 

Lorton, VA 22079] 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 to establish an 

amendment/expansion of an existing tolerance exemption for the biochemical pesticide 

[polyoxin D zinc salt].

 

Pursuant to section 408(d)(2)(A)(i) of FFDCA, as amended, [Kaken Pharmaceutical Co., 

Ltd. ] has submitted the following summary of information, data, and arguments in 

support of their pesticide petition. This summary was prepared by [Conn & Smith, Inc. 

and Kaken Pharmaceutical Co., Ltd.] and EPA has not fully evaluated the merits of the 

pesticide petition. The summary may have been edited by EPA if the terminology used 

was unclear, the summary contained extraneous material, or the summary unintentionally 

made the reader conclude that the findings reflected EPA’s position and not the position 

of the petitioner. 

I. [Kaken Pharmaceutical Co., Ltd.] Petition Summary
2

 [Insert petition number]

A. Product Name and Proposed Use Practices

[Polyoxin D zinc salt is the active ingredient in ENDORSE Water Dispersible 

Granules and other brand name formulations and is proposed for use on all crops both 

pre-harvest and post-harvest according to good agricultural practices. The active portion 

of polyoxin D zinc salt is polyoxin D which is produced by a bacterium that is naturally 

occurring in the soil. Polyoxin D inhibits the growth of phytopathogenic fungal cell wall 

chitin by competitively inhibiting chitin synthetase. Without chitin, susceptible fungi are 

unable to continue growing and infecting plant cells. Polyoxin D zinc salt does not kill 

the fungi; it simply stops the fungal growth. The action of Polyoxin D is highly specific; 

is does not affect bacteria, viruses, or mammals.] 

B. Product Identity/Chemistry 

 1. Identity of the pesticide and corresponding residues. [The CAS name for 

polyoxin D zinc salt is zinc 5-[[2-amino-5-O-(aminocarbonyl)-2-deoxy-Lxylonyl]amino]-1-(5-carboxy-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-1,5-dideoxy-βD-allofuranuronate.]

 2. Magnitude of residues at the time of harvest and method used to determine the 

residue. [The magnitude of the residue has been evaluated as part of the evaluation of the 

nature of the residue in grapes, tomatoes, and lettuce. Each of the crops received three 

pre-harvest treatments at 7-day to 10-day intervals, and the total application rate was the 

maximum seasonal rate. Polyoxin D and uracil-5-carboxilic acid were determined to be 

the primarily metabolites. The sum of the measured polyoxin D and uracil-5-carboxylic 

acid residues were consistently low when the crops were treated at the maximum 

seasonal rate (0.40 mg eq/kg in grape berries harvested 1 day after last treatment, 0.01 mg 

eq/kg in tomatoes harvest 14 days after last treatment, and 0.02 mg eq/kg in head lettuce 

with the outer leaves removed and harvested 7 days after last treatment. These measured 

residues are worst case residues. These nature of the residue studies demonstrated that a 

large percentage of the residue is removed by rinsing the harvested raw agricultural 

commodity with water (84% for grapes harvested 1 day after treatment, 96% for tomatoes 

harvested 1 day after last treatment, and 85% from head lettuce outer leaves harvested 7 

days after last treatment). Also, the nature of the residue studies were conducted in 

greenhouses, and the plants were irrigated so that water did not contact the aerial portion 

of the plant. Under field conditions, residues on crops would be even lower due to 

reduction of residues by rainwater and irrigation water. Also, polyoxin D degrades very 

rapidly in the environment. The half-life is 32.5 days at pH 7 by hydrolysis, 2.3 days by 

aqueous photolysis at pH 7, and 15.9 days in microbially active soil by aerobic soil 

metabolism. Cooking (hydrolysis at elevated temperature) will also reduce the 

magnitude of the residues in the diet.] 

 3. A statement of why an analytical method of detecting and measuring the levels 

of the pesticide residue are not needed. [A tolerance exemption is proposed. Therefore, 

no tolerance enforcement method is proposed.] 
3

C. Mammalian Toxicological Profile

[1. Acute Toxicity: Technical grade polyoxin D zinc salt has very low acute 

toxicity. The acute oral LD50 was determined to be greater than 10,000 mg/kg in rats. 

Polyoxin D is not teratogenic in the rabbit and rat. In a teratology study in rabbits, no 

adverse effects were observed in the pups while body weight reduction was observed in 

the dams at the highest dose tested (800 mg TGAI/kg/day. In a teratology study in rats, 

no treatment related adverse effects were observed in the pups while thickening of the 

limiting ridge of the stomach was observed in dams. Also, no statistically significant 

adverse effects in the offspring were observed in a 2-generation reproduction study at 

dietary intake levels greater than 10,000 mg TGAI. 

2. Subchronic Toxicity: Technical grade polyoxin D zinc salt has very low subchronic 

toxicity. For 90 days, rats were fed a diet containing up to 20,000 ppm technical grade 

polyoxin D zinc salt. The NOAEL was determined to be 2000 ppm (119mg TGAI/kg 

bw/day in males and 135 mg TGAI/kg bw/day in females). At 20,000 ppm, decreased 

body weight gain and decreased food consumption were observed. In a 28-day study to 

evaluate immunotoxicity, female mice were fed a diet containing up to 40,000 ppm 

technical grade polyoxin D zinc salt, and no adverse effects were observed. The NOAEL 

was determined to be approximately 8000 mg TGAI/kg/day. 

3. Chronic Toxicity: Technical grade polyoxin D zinc salt has very low chronic toxicity. 

For 24 months, rats were fed a diet containing up to 5% technical grade polyoxin D zinc 

salt and evaluated the toxicity, including oncogenicity. No statistically significant effects 

were observed at the highest dose tested. The NOAEL was determined to be 2,058.7 mg 

TGAI/kg bw/day in males and 2,469.8 mg TGAI/kg bw/day in females. 

4. Mutagenicity: Based upon the weight of evidence, technical grade polyoxin D zinc 

salt is not mutagenic. Technical grade polyoxin D zinc salt was determined to be nonmutagenic in an Ames test, a Rec-assay with Bacillus subtilis H-17 and M-45, and a host 

mediated Assay with S. typhimurium G-46 in mice. Equivocal results were obtained in a 

chromosome aberration study, and data indicating weak mutagenicity were obtained in a 

second Ames test. However, in a repeat chromosome aberration study, technical grade 

polyoxin D zinc salt was determined to be non-mutagenic. Also, in a repeat Ames study, 

technical grade polyoxin D zinc salt was determined to be non-mutagenic. Even more 

importantly, in an in vivo (whole animal) study, technical grade polyoxin D zinc salt was 

determined to be not mutagenic. Technical grade polyoxin D zinc salt was determined to 

by not mutagenic at the highest dose tested (2000 mg TGAI/kg) in the mouse 

micronucleus test. Most importantly, technical grade polyoxin D zinc salt is not 

teratogenic and not oncogenic. These results are consistent with a non-mutagenic 

material.] 

D. Aggregate Exposure

 1. Dietary exposure. [Dietary exposure to polyoxin D zinc salt residues resulting 

from both pre-harvest and post-harvest treatment of crops according to good agricultural 
4

practices will be very low.]

 i. Food. [Based upon (a) the low measured residues in crops treated pre-harvest in 

a greenhouse at the maximum seasonal rate, (b) significant measured residue reduction 

resulting from rinsing with water, and (c) rapid environmental degradation of polyoxin D, 

dietary exposure to polyoxin D zinc salt residues resulting from crops treated pre-harvest 

according to good agricultural practice will be low. Residues resulting from treatments 

applied post-harvest will similarly be significantly reduced by rinsing the raw agricultural 

commodity with water. In addition, cooking will further reduce these low level residues 

to very low level residues.]

 ii. Drinking water. [Residues of polyoxin D zinc salt will be very low. Polyoxin 

D zinc salt degrades rapidly under normal environmental conditions. The half-life is 32.5 

days at pH 7 by hydrolysis, 2.3 days by aqueous photolysis at pH 7, and 15.9 days in 

microbially active soil by aerobic soil metabolism.]

 2. Non-dietary exposure. [Polyoxin D zinc salt is registered to control fungal 

diseases of turf. The use on turf was previously estimated to result in very low nondietary risk, including hand-to-mouth exposure to infants and children.]

E. Cumulative Effects

 [Polyoxin D zinc salt is not known to share a toxicological mode of action with 

any other pesticide.]

F. Safety Determination

 1. U.S. population. [Based upon the combination of very low mammalian toxicity 

and very low aggregate exposure, the sum of all registered uses and potential new uses of 

polyoxin D zinc salt to control or suppress fungal diseases in crops according to good 

agricultural practices has a reasonable certainty of no harm to the U.S. population.]

 2. Infants and children. [The available data indicate that polyoxin D zinc salt has 

very low toxicity, including to infants and children. No increased sensitivity by infants or 

children was indicated in any of the laboratory studies. Therefore, the sum of all 

registered uses and potential new uses of polyoxin D zinc salt to control or suppress 

fungal diseases in crops according to good agricultural practices has a reasonable 

certainty of no harm to infants and children.] 

G. Effects on the Immune and Endocrine Systems 

 [In a 28-day study to evaluate immutoxicity (splenic antibody study), female 

mice were fed a diet containing up to 40,000 ppm technical grade polyoxin D zinc salt, 

and no adverse effects were observed. The NOEL was determined to be approximately 
5

8000 mg TGAI/kg bw/day. No evidence of endocrine system effects was observed in the 

subchronic, chronic, teratology, or reproduction studies.] 

H. Existing Tolerances

 [There is an existing exemption from the requirement of a tolerance for residues 

of polyoxin D zinc salt on almonds, cucurbits vegetables, fruiting vegetables, ginseng, 

grapes, pistachios, pome fruits, potatoes, and strawberries when applied as a biochemical 

pesticide to control and suppress fungal diseases. See 40 CFR §180.1285.]

I. International Tolerances

 [There are no current CODEX MRLs or other international tolerances for 

polyoxin D zinc salt or polyoxin D. Polyoxin D zinc salt is registered for food uses in 

Japan, Korea, Taiwan, and Mexico, and the regulatory authorities in these countries have 

each determined that no tolerance (MRL) is needed.]