EPA REGISTRATION DIVISION COMPANY 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 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.

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 Cosmetic 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 interest for end use products.] EPA has determined that the 

petition contains data or information regarding the elements set forth in section 408 (d)(2) 

of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data 

at this time or whether the data supports granting 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-trimethylethanolammonium 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 positive functional role in 

mammalian systems. The majority of the literature for choline focuses on its 

biological function rather than toxicity or hazard. Choline-deficient diets are 

associated with numerous adverse effects. The NAS has set established human 

dietary intake recommendations by age group 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 Panel on Folate, Other B Vitamins, and 

Choline and Subcommittee on Upper Reference Levels of Nutrients, Food and 

Nutrition, 1998.). The choline chloride form was recently characterized by the EPA 

as having low toxicity (US 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).] 

 1. Acute toxicity. [High end exposure to choline 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 choline is genotoxic. Studies with 

choline chloride show it did not have any 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 benefit from higher exposure to choline. In a 

recent review, EPA concluded that choline has been shown to have positive effects 

on development (US 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). ]

 4. Subchronic toxicity. [An OECD repeat-dose study with 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 associated with increased incidence of liver 

cancer and increased sensitivity to carcinogenic chemicals in rodents. No 

hepatocellular carcinomas were reported in rodents supplemented with choline for 

28 weeks or two years.] 

 6. Animal metabolism. [The absorption, metabolism and excretion of choline 

are well summarized by the NAS. Choline is known to be oxidized to form betaine 
3

in the liver and kidney with the methyl groups 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 kidney to form betaine. Also prior to 

absorption by the gut, some choline is metabolized by bacteria to form betaine and 

methylamines).] 

 7. Metabolite toxicology. [Specific study information for choline is not 

available, nor deemed necessary due to the essential nutrient role of choline.]

 8. Endocrine disruption. [The potential for choline 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 endocrine disruptors (US 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 assessment without traditional animal and 

FQPA factors is proposed. The translation 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 most of the older subpopulations the values 

center around 50 mg/kg/day]. Therefore, the 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 ingredients 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 included. 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 drinking 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 prominent 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 action, 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 there 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 dietary limits are established in humans by 

age without need for additional animal extrapolations 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.]