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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. 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] 

EPA has received a pesticide petition ((73049-XXX]) from [Valent Biosciences 

Corp.], [870 Technology Way, Libertyville, 11. 60048] proposing, 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. 

(Options (pick one) 

1. by establishing a tolerance for residues of 

2. to establish an exemption from the requirement of a tolerance for 

3. to establish an amendment/expansion of an existing tolerance exemption 

for the 

(Options (pick one) 

1. microbial pesticide [insert name of active ingredient] 

2. biochemical pesticide [methyl salicylate, also known as oil of wintergreen] 

3. plant-pesticide [insert name of active ingredient] in or on [insert 
commodities]. 

Pursuant to section 408(d)(2)(A)(i) of FFDCA, as amended, [Valent Biosciences 

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

support of their pesticide petition. This summary was prepared by [Valent Biosciences 

Corp.] 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. [Valent Biosciences Corporation! Petition Summary 

[XX-XXXX] 

A. Product Name and Proposed Use Practices 

[Methyl Salicylate, also known as oil of wintergreen, for use in or on all 

agricultural commodities as an SAR inducer, to help prevent and control certain 

bacterial diseases] 

B. Product Identity/Chemistry 

1. Identity of the pesticide and corresponding residues. [Methyl salicylate 

(MeSA) is a natural compound produced in multiple plants such as tea, rice, 

soybeans, peppers and tomatoes in small quantities. Methyl salicylate has 

widespread use in consumer products such as cosmetics, tooth paste, mouth rinses 

and is used as an analgesic in the treatment of muscle and joint pain. It also has a 

long history of being used as a flavoring in tobacco and foods such as candy, 

beverages, chewing gum and baked goods. 

Additionally methyl salicylate is naturally produced by plants as a critical signal to 

induce an immune response in plants. ] 

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

residue. [Due to the high vapour pressure of methyl salicylate, the natural levels of 

methyl salicylate on plants, the literature studies indicating half-lives of a few 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 of toxicological 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 in both tomato 

and pepper. The analytical method for the assay of Methyl Salicylate and Salicylic 

Acid is by gas chromatography with mass-selective detection. Methyl Salicylate 

will not result in residues that are of toxicological concern, as the residue studies 
clearly show only natural background levels of methyl salicylate and its metabolite, 

salicylic acid, after applications even at time zero. ] 

C. Mammalian Toxicological Profile 

[ Acute Oral toxicity 

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% of methyl salicylic acid in 

their diet, corresponding to approximately 0, 50 and 500 mg/kg bw, a significant 

reduction in growth rate was observed at dietary levels corresponding at 

approximately 

500 mg/kg bw. 

The feeding of methyl salicylate to rats for 2 years at levels of 0 .1, 0 .5, 1.0 and 2.0% 

of the 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 less pronounced 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, 1535 and 

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), CHL cell cultures were exposed to methyl salicylate at 3 concentrations 

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 of 20 rats were fed 500, 

1,500, 3,000 or 5,000 ppm methyl salicylate in the diet for 3 generations. 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 of liveborn progeny, viability Index, the number of progeny surviving at 4 

days and the number surviving to weaning at dose levels of 3,000 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, starting at 1500 ppm, in the average litter size, number of liveborn 

progeny and the number of day 4 survivors. No grossly visible abnormalities were 

observed in external examinations of new borns 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 g body weight at sp cific times during the period of gestation from 

day 7 hour 9 to day 7 hour 22, the frequency of cranium bitfida in embryos at day 9 

ranged from lU-73%, compared to 11% in controls. The critical importance of 

timing was indicated by the fact that treatment at hour 21 resulted in a significant 

frequency of defects, while treatment just one hour later, at hour 22, induced a 

frequency of defects 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 of offspring. 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 of approximately 30 g of 
salicylates Ingested by a 60 kg female during early gestation. 

D. Aggregate Exposure 

1. Dietaiy exposure. [Dietary exposure from methyl salicylate use as a 

pesticide will be orders of magnitude below the use of methyl 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 will be 

orders of magnitude below the use of methyl salicylate as a food flavouring agent. 

Further, MeSa is naturally present in crops, and in fields planted with these crops, 

and there is a long history and prevalence of methyl salicylate in human diets. No 

additional dietary exposure will arise from the pesticidal application of MeSa 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 is unlikely because 

potential use sites are commercial agricultural. Methyl salicylate is used in muscle 

ointments, so that use can present potential non-dietary exposure.] 

E. Cumulative Effects 

[The toxicity mode of action of methyl salicylate is the same as for salicylic 

acid, but no food pesticide uses exist for salicylic acid. ] 

F. Safety Determination 

1. U.S. population. [There is reasonable certainty that no harm 

will result from aggregate exposure to residues of methyl salicylate to the U.S. 

population. This includes all anticipated dietary exposures and all other exposures 

for which there is reliable information.] 

2. Infants and children. [Petitioner believes that EPA has sufficient data to 

address the issue of the potential additional sensitivity of infants 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 of this 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 

levels higher 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 increased 
potential exposures..] 

G. Effects on the Immune and Endocrine Systems 

[Methyl salicylate has been studied in several tests of reproductive and 

developmental effects, including niultigenerational studies. In addition, the 

pathology of endocrinesensitive tissues and organs has been evaluated following 

repeated (i.e., subchronic) and long-term (i.e., chronic) exposures. These studies 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 effect produced by 

a naturally occurring estrogen or other endocrine effects.) 

H. Existing Tolerances Oil of wintergreen is exempt from the requirement of a 

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 of a tolerance 

The biochemical pesticide methyl salicylate is exempt from the requirement of a 

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. 

[• 

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I. International Tolerances 

[International tolerances are available as flavorings and medicinal uses but 

not for pesticidal uses 

[. EFSA(EFSA Journal 2012;10(7):2785; pennitted the use of MeSa at: 

Maximum safe concentration in feed of flavourings for different target 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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