EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [ P.V. Shah, 703-308-1846 ]

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.

TEMPLATE:

[Dow AgroSciences, LLC]

[PP 0E7686]

EPA has received a pesticide petition (PP 0E7686) from [Dow AgroSciences, LLC], [9330 Zionsville Rd, Indianapolis, IN, 46268] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosme tic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.

to establish an exemption from the requirement of a tolerance for

[choline hydroxide CAS 123-41-1; under 40 CFR 180.920 when used as an inert ingredient in a pesticide formulation. A limitation for use as a neutralizing agent in herbicide-only products is proposed. Based on the proposed use, the choline cation is the species of in terest for end use products.] EPA has determined that the petition contains data or info rmation regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully eval uated the sufficiency of the submitted data at this time or whether the data supports gr anting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry [Specific residue information is not available for choline hydroxide; however, choline (N,N,N-trim ethylethanolammonium cation) is an essential nutrient found in many foods, including milk, liver, eggs, peanuts, soybeans, beef, cauliflower, kale, and cabbage

. ]

1. Plant metabolism. [omit -per above, not needed .]

2. Analytical method. [omit -per above, not needed.]

3. Magnitude of residues. [omit -per above, not needed .]2

B. Toxicological Profile [Overall, choline plays a posi tive functional role in mammalian systems. The majority of th e literature for choline focuses on its biological function rather th an toxicity or hazard. Choline-deficient diets are

associated with numerous adverse effects. The NAS has set established human dietary intake recommendations by age gr oup which can be employed as a safety threshold for human exposure (Institute of Medicine, National Academy of Sciences USA, Chapter 12, A Report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Pa nel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Referen ce Levels of Nutrients, Food and Nutrition, 1998.). The choline chloride form was recently characterized by the EPA as having low toxicity (US EPA, Decisi on Document for Petition Number 8E7387; Choline Chloride, CAS Reg No 67-48- 1, Docket Number: EPA-HQ-OPP-2008-0671- 0004, October 16, 2009).]

1. Acute toxicity. [High end exposure to cholin e has been reviewed by the NAS and is covered in the established daily UL (Upper Limits) for human dietary consumption. The UL values range from 1 g/day for young children to 3.5 g/day for pregnant adults. ]

2. Genotoxicty. [There is no indication that chol ine is genotoxic. Studies with

choline chloride show it did not have an y mutagenic potential in several in vitro assays, including Ames assays, cytogenic assays, sister chromatid exchange (SCE) assays, and a gene conversion assay.]

3. Reproductive and developmental toxicity. [No adverse differential sensitivity for young children is noted in the NAS UL dietary recommendations. The daily recommendations for AI (adequate intake) by infants is 18 mg/kg/day as compared to 7 mg/kg/day for adults. Children benefi t from higher exposure to choline. In a recent review, EPA concluded that choline ha s been shown to have positive effects on development (US EPA, Decision Docu ment for Petition Number 8E7387; Choline Chloride, CAS Reg No 67-48-1, Dock et Number: EPA-HQ-OPP-2008-0671-0004, October 16, 2009)

. ]

4. Subchronic toxicity. [An OECD repeat-dose study wi th no adverse effects in mice with choline chloride at 200 mg/kg/day is confirmatory of the NAS recommendations for dietary choline.]

5. Chronic toxicity. [There is a low likelihood of cancer risk with choline exposure. In fact, the general concern for cancer revolves around deficiency in choline. Choline-deficiency has been asso ciated with increased incidence of liver cancer and increased sensitivity to carci nogenic chemicals in rodents. No hepatocellular carcinomas were reported in rodents supplemented with choline for 28 weeks or two years.]

6. Animal metabolism. [The absorption, metabolis m and excretion of choline are well summarized by the NAS. Choline is known to be oxidized to form betaine3

in the liver and kidney with the methyl gr oups of betaine scavenged and reused in single-carbon metabolism. Some choline has been observed in the urine unchanged, but the majority is oxidized within the ki dney to form betaine. Also prior to absorption by the gut, some choline is me tabolized by bacteria to form betaine and methylamines).]

7. Metabolite toxicology

. [Specific study information for choline is not available, nor deemed necessary due to th e essential nutrient role of choline.]

8. Endocrine disruption

. [The potential for cholin e to interact with the endocrine system has not been specifically evaluated. However, based on the available information and the importance of choline in the diet for optimal health and well-being, endocrine disruption is not a likely concern. EPA recently noted that choline chloride and it’s metabolites are not known endocrine disruptors nor are they related to any class of known e ndocrine disruptors (U S EPA, Decision Document for Petition Number 8E7387; Choline Chloride, CAS Reg No 67-48-1, Docket Number: EPA-HQ-OPP- 2008-0671-0004, October 16, 2009).]

C. Aggregate Exposure

1. Dietary exposure. [Based on the health benefits for humans provided by dietary choline, a comparative risk a ssessment without traditional animal and FQPA factors is proposed. The translatio n of upper limit values to mg/kg/day using specific body weights by subpopulation causes the UL values to vary slightly, but the total range is 43 to 76 mg/kg/day and for mo st of the older subpopulations the values center around 50 mg/kg/day]. Therefore, th e assessment uses the NAS dietary UL values in humans as safety thresholds with values of 76, 50 and 43 mg/kg/day for children, adults and youth, respectively.]

i. Food. [Inert exposure predicted from the EPA Inert’s Branch dietary exposure model IDEEM model is used. I-DEEM uses a screening level dietary

assessment of 57 of the most “significant” active ingredie nts as surrogates for inerts within the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCIDTM, Version 2.14). Exposure from food, animal commodities and drinking water are in cluded. The herbicide-only I-DEEM calculations (US EPA meeting with JITF on March 6, 2008) predicts Children 1-2 years old are found to be the most exposed subpopulation with an estimated exposure of 0.2 mg/kg/day.

The dietary (food plus drinki ng water) exposures for inert use of choline hydroxide are compared to the NAS dietary UL values in humans. The potential increase in choline exposure from use in herbicide formulations is <1% of recommended UL

limits based on human nutritional standards for all subpopulations.]

ii. Drinking water. [Drinking water estimates have been included in the IDEEM model.]4

2. Non-dietary exposure

. [No consumer uses of choline hydroxide have been identified. For choline, no promin ent consumer uses other than dietary supplements and nutraceuticals are known. EPA recently approved choline chloride for pesticidal product use as a “solvent” under CFR 180.920 (US EPA, Federal Register, Vol. 75 , No. 3, January 6, 2010, Final Rule, EPA–HQ–OPP–2008– 0671; FRL-8802–4.)]

D. Cumulative Effects

[For the purposes of this tolerance acti on, it is not assumed that choline has a common mechanism of toxicity with other substances.]

E. Safety Determination

1. U.S. population. [For the general population, the estimated increased exposure from the proposed use is <1% of the human dietary UL. Based on this assessment, Dow AgroSciences believes the re is a reasonable certainty that no harm will result to the US population from the aggregate exposure to choline hydroxide

when used as an inert in herbicide formulations.]

2. Infants and children

. [A FQPA safety factor is not needed as supported by the fact that: 1] there is no indication of adverse differential sensitivity for children in the dietary recommendations; 2) the dietar y limits are established in humans by age without need for additional animal ex trapolations and 3) the potential added dietary exposure to choline as assumed by IDEEM is < 0.2 mg/kg/day, which is far less than the daily dietary recommendations for choline.

F. International Tolerances

[There are no known tolerances.]