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EPA BIOPESTICIDESAND 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 inpreparing 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. Simpiy 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: [Valent Biosciences Corp.] (73048-XXX] EPAhasreceived apesticide petition ((73049-XXX]) from [Valent Biosciences Corp.], [870 Technology Way,Libertyville, 11.60048]proposing,pursuant to section 408(d) oftheFederal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend40 CFRpart 180. (Options (pick one) 1.by establishing atolerance forresidues of 2. to establish an exemption from therequirement ofatolerance for 3. to establish an amendment/expansion ofan existing tolerance exemption for the
(Options (pick one) 1.microbial pesticide [insert name ofactive ingredient] 2.biochemical pesticide [methyl salicylate, also known as oil ofwintergreen]

3.plant-pesticide [insert name ofactive ingredient] inoron [insertcommodities]. Pursuantto section408(d)(2)(A)(i) of FFDCA, as amended, [Valent Biosciences Corp.] has submitted the following summary ofinformation,data, and arguments in support oftheirpesticidepetition. This summary was preparedby [Valent Biosciences Corp.] andEPA has not fully evaluatedthe merits ofthepesticide petition. The summary mayhavebeen edited by EPA ifthe terminologyused wasunclear, the summary contained extraneous material, or the summaryunintentionally made thereader conclude thatthe findingsreflected EPA's position and notthe position ofthepetitioner. I. [Valent Biosciences Corporation! Petition Summary [XX-XXXX] A.ProductName andProposed UsePractices [Methyl Salicylate, also known as oil ofwintergreen, for use in or on all agricultural commodities as an SAR inducer, to help prevent and control certain bacterial diseases]

B.ProductIdentity/Chemistry 1.Identityofthepesticide and corresponding residues. [Methyl salicylate (MeSA) is anatural compound produced inmultiple plants such as tea, rice, soybeans, peppers and tomatoes insmall quantities. Methyl salicylate has widespread usein consumer products such as cosmetics, tooth paste, mouth rinses and is used as an analgesic inthe treatment ofmuscle andjoint pain. It also has a long history ofbeing used as a flavoring intobacco and foods such as candy, beverages, chewing gum and baked goods. Additionally methyl salicylate isnaturally produced by plants as a critical signal to induce animmune response in plants. ] 2.Magnitudeofresiduesat thetimeofharvestandmethodusedtodeterminethe residue. [Due to the high vapour pressure ofmethyl salicylate, the natural levels of methyl salicylate on plants, the literature studies indicating half-lives ofafew hours on applied plants, and the residue studies supplied by the registrant the petitioners believes that when methyl salicylate is applied on crops methyl salicylate will not result in residues oftoxicological concern! 3. A statement of why an analytical method of detecting and measuring the levels of the pesticide residue are not needed. [The petitioner has validated residue methods inboth tomato and pepper. The analytical method for the assay ofMethyl Salicylate and Salicylic Acidis by gas chromatography with mass-selective detection. Methyl Salicylate will not result in residues that are of toxicological concern, as the residue studiesclearly show only natural background levels ofmethyl salicylate and its metabolite,

salicylic acid, after applications even at time zero. ] C.Mammalian Toxicological Profile [ AcuteOraltoxicity

Animal Route LD50 (mg/kg body-weight)

Mouse oral 1110 Rat oral 887 Rat oral 1250 Guinea-pig oral 700 Guinea-pig oral 1060 Guinea-pig s.c. 1500 Rabbit oral 1300 Rabbit oral 2800 Dog oral 2100 Methyl salicylate is an eye and skin irritant but not a skin sensitizer.

Long Term Feeding Studies: Rats given methyl salicylic acid in their diet for up to 10 weeks at a dose of approximately 1000 mg/kg bw showed reduced growth and reduced chondroclastic and osteoclastic activity. Similar findings were not observed in animals receiving approximately 450 mg/kg bw or less. In a 17-week dietary study, rats were fed 0, 0.1 and 1% ofmethyl salicylic acid in their diet, corresponding toapproximately 0, 50 and 500 mg/kgbw, a significant reduction in growth rate was observed at dietary levels corresponding at approximately 500 mg/kgbw. The feeding ofmethyl salicylate to rats for 2years at levels of0 .1, 0 .5, 1.0 and 2.0% ofthe diet produced statistically significant growth retardation in the rats on the 1 and 2% diets

.There was an increase in cancellous bone in all bones examined from the rats on the 2% diet.This was lesspronounced in degree and incidence in the rats on the 1% diet. No effects at 0.1 % Mutagenicity:Studies similar to OECD Guidelines 471 (Bacterial Reverse mutation Assay) and

473 (In vitro Mammalian Chromosome Aberration Test). In the reverse gene mutation test with Salmonella typhimurium strains TA 92, 94, 98, 100, 1535and 1537 exposed to methyl salicylate, duplicate plates were used for six concentrations in the presence or absence of mammalian metabolic activation (liver microsomal fractions, S9,from Fisher rats). Methyl salicylate was non-mutagenic under the assay conditions. In the mammalian cell cytogenetic assay (chromosomal aberration), CHLcell cultures were exposed to methyl salicylate at 3concentrations up to 0.25 mg/ml for 24 or 48 hours without metabolic activation. The cytotoxic concentration was defined as the dose which induced 50% cell growth inhibition. Methyl salicylate did not induce a clastogenic effect. For sister chromatid exchange in several Chinese hamster cell lines and in human lymphocytes Negative results were obtained in this assay with methyl salicylate Reproductive: A variety of reproductive effects were noted when groups of20 rats were fed 500, 1,500, 3,000 or 5,000ppm methyl salicylate in the diet for 3generations. No significant decrease was observed in the fertility index at any dosage level or generation, but there were notable decreases observed in average litter size, average number ofliveborn progeny, viability Index, the number of progeny surviving at 4 days and the number surviving to weaning at dose levels of3,000 and 5,000 ppm methyl salicylate. These decreases were most significant in the second generation. Combined results from all 3 generations indicated an apparent dose-related response, startingat 1500ppm, in the average litter size, number ofliveborn progeny and the number of day 4 survivors. No grossly visible abnormalities were observed in external examinations of newborns or weanlings from any generation; autopsies and histological examinations of. third generation weanlings revealed no abnormalities or evidence of toxicity. Variations in the teratogenic response in hamsters to methyl salicylate was affected by differences in fetal age which apparently correspond to different intrauterine positions. When pregnant hamsters were given oral doses of 175-225 mg methyl salicylate per 100 gbody weight at sp cifictimes during the period of gestation from day 7 hour 9 to day 7 hour 22, the frequency ofcranium bitfida in embryos at day 9 ranged from lU-73%, compared to 11% in controls. The criticalimportance of timing was indicated by the fact that treatment at hour 21 resulted in a significant frequency ofdefects, while treatment just one hour later, at hour 22, induced a frequency ofdefects not statistically different from the control value. It should be noted that the doses of methyl salicylate which induced teratogenic effects in these studies were close to dose levels which are lethal to the embryo and toxic to the dam, thereby decreasing the expected yield ofoffspring. Also these doses were, on a weight basis, far greater than therapeutic human doses. Takacs and Warkany (1968) estimated that an equivalent dose in humans to that inducing a teratogenic response in rats would require intake ofapproximately 30 g ofsalicylates Ingestedby a 60kg female during early gestation.

D.AggregateExposure 1.Dietaiy exposure. [Dietary exposure from methyl salicylate use as a pesticide willbe orders ofmagnitude below the use ofmethyl salicylate as a food flavouring agent. No additional dietary exposure will arise from the pesticidal application of MeSa as to residues are created by the application, j 1.Food. [Dietary exposure from methyl salicylate use as a pesticide willbe orders ofmagnitude below the use ofmethyl salicylate as a food flavouring agent. Further, MeSa isnaturally present in crops, and in fields planted with these crops, and there is a long history and prevalence ofmethyl salicylate in human diets. No additional dietary exposure will arise from the pesticidal application ofMeSa as to residues are created by the application. [ ii. Drinking water. [Methyl salicylate is not expected to enter drinking water systems. [ 2. Non-dietary exposure. [The potential for non-dietary exposure to methyl salicylate as a pesticide for the general population isunlikely because potential use sites are commercial agricultural. Methyl salicylate is used in muscle ointments, so that use can present potential non-dietary exposure.] E. CumulativeEffects [The toxicity mode of action of methyl salicylate is thesame as forsalicylic acid, but no food pesticide uses exist for salicylic acid. ] F. Safety Determination 1. U.S. population. [There isreasonable certainty that no harm willresult from aggregate exposure to residues ofmethyl salicylate to the U.S. population.This includes all anticipated dietary exposures and all other exposures for which there is reliable information.] 2. Infants andchildren. [Petitioner believes that EPA has sufficient data to address the issue ofthe potential additional sensitivity ofinfants and children to pesticidal methyl salicylate residues. Petitioner points to the long history of use of this substance as a flavoring in foods, and the data submitted to the Agency in support ofthis petition. Reproductive and developmental effects have been found in toxicology studies for methyl salicylate; however, these adverse effects occurred at exposure levels that were also maternally toxic or at exposure levelshigher than those producing other adverse effects following chronic exposure. Petitioner believes that infants and children are not differentially sensitive to methyl salicylate either by virtue of increased toxicological susceptibility' or increasedpotential exposures..]

G.Effects on theImmune andEndocrine Systems [Methyl salicylate has been studied in several tests of reproductive and developmental effects, including niultigenerational studies. In addition, the pathology ofendocrinesensitive tissues and organs has been evaluated following repeated (i.e., subchronic) and long-term (i.e., chronic) exposures. Thesestudies are sufficient to detect endocrine effects. No such effects were reported in any of these studies. Therefore, Petitioner concludes that pesticidal uses of methyl salicylate are unlikely to have an effect in humans that is similar to an effectproduced by a naturally occurring estrogen or other endocrine effects.) H.Existing Tolerances Oil ofwintergreen is exempt from the requirement ofa tolerance when used in accordance with good agricultural practice as an inert (or occasionally active) ingredient in pesticide formulations applied to growing crops or to raw agricultural commodities (40 CFR 180.1001(c)). 180.1189 Methyl salicylate; exemption from the requirement ofa tolerance The biochemical pesticide methyl salicylate is exempt from the requirement ofa tolerance for residues in or on food or feed when used as an insect repellant in food packaging and animal feed packaging at an application rate that does not exceed 0.2 mg of methyl salicylate per square inch of packaging materials. [• 

### 1 I.International Tolerances [International tolerances areavailable as flavorings and medicinal uses but not for pesticidal uses [. EFSA(EFSAJournal 2012;10(7):2785; pennitted the use ofMeSa at:

Maximum safe concentration in feed offlavourings for differenttarget animals (mg/kg) Veal Calves Salmonids Cattle Pigs Sows Dairy cows Turkeys Piglets 25 25 25 17 17 16 15 10

Chicken Laying hens Cats Dogs 88 25 30 

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