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EPA BIOPESTICIDES AND POLLUTI ON PREVENTION DIVISION

COMPANY NOTICE OF FILING FOR PE STICIDE 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 p reparing the pesticide petition. In

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

maintain the outline. Please do not chan ge 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 temp late 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 agri cultural 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 Summary2

[Insert petition number]

A. Product Name and Proposed Use Practices

[Polyoxin D zinc salt is the active ingr edient 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 pol yoxin D which is produced by a b acterium that is naturally occurring in the soil. Polyoxin D inhibits the growth of phytopa thogenic fungal cell wall chitin by competitively inhibiting chitin synthe tase. 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 pestic ide 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(2 H )-pyrimidinyl)-1,5-dideoxy- β

D-allofuranuronate.]

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

residue. [The magnitude of the residue has been ev aluated as part of the evaluation of the nature of the residue in grapes, tomatoes, a nd 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 remove d by rinsing the harves ted raw agricultural commodity with water (84% for grapes harves ted 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 studie s were conducted in greenhouses, and the plants were irrigated so that water did not cont act the aerial portion of the plant. Under field conditions, resi dues on crops would be even lower due to reduction of residues by rainwater and irrigati on 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 activ e soil by aerobic soil metabolism. Cooking (hydrolysis at elevat ed 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 LD 50 was determined to be greater than 10,000 mg/kg in rats. Polyoxin D is not teratogenic in the rabbit a nd rat. In a terato logy 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 obs erved in the pups while thickening of the limiting ridge of the stomach was observed in dams. Also, no stat istically significant adverse effects in the offspring were obs erved in a 2-generati on reproduction study at dietary intake levels gr eater than 10,000 mg TGAI.

2. Subchronic Toxicity : Technical grade polyoxin D zi nc salt has very low subchronic toxicity. For 90 days, rats were fed a di et containing up to 20, 000 ppm technical grade polyoxin D zinc salt. The NOAEL was dete rmined to be 2000 ppm (119mg TGAI/kg bw/day in males and 135 mg TGAI/kg bw/d ay in females). At 20,000 ppm, decreased body weight gain and decreased food consump tion were observed. In a 28-day study to evaluate immunotoxicity, female mice were fed a diet contai ning up to 40,000 ppm technical grade polyoxin D zinc salt, and no adverse effects were observed. The NOAEL was determined to be approxi mately 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 containi ng up to 5% technical grade polyoxin D zinc

salt and evaluated the to xicity, 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 polyoxi n 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 indicatin g 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 test ed (2000 mg TGAI/kg) in the mouse micronucleus test. Most importantly, t echnical grade polyoxin D zinc salt is not teratogenic and not oncogenic. These resu lts 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 treatme nt of crops according to good agricultural4

practices will be very low.]

i. Food. [Based upon (a) the low measured residu es in crops treate d 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 significan tly 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 e nvironmental conditions. The half-life is 32.5 days at pH 7 by hydrolysis, 2.3 days by aque ous 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 re gistered to control fungal diseases of turf. The use on turf was prev iously estimated to result in very low nondietary risk, including hand-to-mout h exposure to infants and children.]

E. Cumulative Effects

[Polyoxin D zinc salt is not known to shar e 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 us es 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 cert ainty 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 child ren. No increased sensitivity by infants or children was indicated in any of the laborat ory 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 immut oxicity (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 approximately5

8000 mg TGAI/kg bw/day. No evidence of endoc rine system effects was observed in the subchronic, chronic, terato logy, or reproduction studies.]

H. Existing Tolerances

[There is an existing exemption from th e requirement of a tolerance for residues of polyoxin D zinc salt on almonds, cucurbit s 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 regu latory authorities in these countries have each determined that no tolerance (MRL) is needed.]