1

 

October 16, 2009

MEMORANDUM

SUBJECT: Decision Document for Petition Number 8E7387; 

Choline Chloride, CAS Reg. No 67-48-1 

 

FROM: Deirdre Sunderland, Industrial Hygienist

 Inert Ingredient Assessment Branch (IIAB) 

 Registration Division (7505P) 

TO: PV Shah, Chief 

 Inert Ingredient Assessment Branch (IIAB) 

 Registration Division (7505P) 

EXCUTIVE SUMMARY

Choline chloride is a quaternary ammonium salt which dissociates in water 

resulting in a positively charged quaternary hydroxyl alkylammonium ion and a 

negatively charged chloride ion. Choline is an essential component of the human 

diet and acts as a precursor to acetylcholine, phospholipids, and the methyl 

donor betaine. It is important for the structural integrity of cell membranes, 

cholinergic neurotransmission, transmembrane signaling, methyl metabolism, 

and lipid and cholesterol transport and metabolism. 

Choline is found naturally in foods in both esterified forms and as free 

choline. Historically, it has been used as a food additive for animal husbandry, in 

plant growth regulator formulations, and as food supplements for humans. 

Choline was officially made an “essential nutrient” in 1998 and adequate intake 

(AI) level were established (women-425 mg/day, pregnant women- 450 mg/day, 

men and lactating women- 550 mg/day). The Daily Upper Intake Level for choline 

is 3.5 grams for adults. Research indicates that many individuals are not getting 

enough choline, with daily intake levels far below the AI.

Chloride is a binary compound of chlorine; a salt of hydrochloric acid. 

Chloride is the major extracellular anion and contributes to many body functions 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 

OFFICE OF PREVENTION, 

PESTICIDE, AND TOXIC SUBSTANCES 
2

including the maintenance of osmotic pressure, acid-base balance, muscular 

activity, and the movement of water between fluid compartments. The World 

Health Organization has performed two assessments which determined that from 

a toxicological point of view, there were no concerns for the chloride ion. It was 

considered to be naturally-occurring and a normal participant of animal and 

human metabolism. 

Choline chloride has demonstrated a low acute oral toxicity with LD50

values for rats ranging from 3150 to ≥ 6000 mg/kg and LD50 for mice in the range 

of 3900 to 6000 mg/kg. Although appropriate animals studies are lacking for 

acute dermal toxicity, an in vitro percutaneous absorption study performed under 

occluded and unoccluded conditions showed that choline chloride is expected to 

have a low potential for percutaneous absorption. Acceptable acute inhalation 

studies are not available. 

Studies were conducted in the early 1960’s which resulted in only slight 

transient irritation of the skin and eye; however, these studies were not 

performed under OECD guidelines and therefore the degree of irritation is not 

classifiable under the Globally Harmonized System of Classification and Labeling 

of Chemicals (GHS). Choline chloride is not expected to cause skin sensitization. 

Repeat dose animal studies on choline chloride are limited. One study in 

mice, evaluated the impact of 200 mg/kg/day choline chloride given orally or 

intranasally for 28 days. No adverse effects were observed with regards to body 

weight, food and water consumption, hematology, clinical biochemistry (Urea, 

BUN, HDL, TC, ALT, AST, and creatinine), or histopathology of various organs 

(lung, heart, liver, spleen, and kidney). Results from intranasal exposure to 

choline chloride were comparable with their respective controls and to other 

treatment groups. The NOAEL for oral and intranasally administered choline 

chloride is ≥ 200 mg/kg/day. 

A 72-week feeding study in rats administered 500 mg/kg/day of choline 

chloride and observed the animals for 30 weeks post exposure. There were no 

significant difference between the control and treated group in relation to body 

weights, relative liver weight, survival rates, and the number of neoplastic liver 

nodules, hepatocellular carcinomas, lung tumors, leukemia, or other tumors. This 

study resulted in a NOAEL of 500 mg/kg. 

 Choline is a precursor to the vital neurotransmitter acetylcholine. Studies 

show that choline has beneficial effects on the nervous system and memory. 

Choline is necessary to promote proper development in the fetus and infant and 

prevent cognitive problems. Choline chloride not expected to cause neurotoxicity. 

 Choline chloride is not a known endocrine disruptors nor is it or its 

metabolites related to any class of known endocrine disruptors. Based on the 
3

results of the in vitro and in vivo studies the Agency concluded that choline 

cloride is not expected to be carcinogenic or mutagenic. 

 

Since the 1930’s choline chloride has been used as a widespread nutrient 

in animal feed without adverse effects reported on fertility or teratogenicity. The 

Food and Drug Administration (FDA) requires choline be added to non-milk 

based infant formulas at a minimum concentration of 7 mg for every 100 

kilocalories (21 CFR 107.100). Although one study did show developmental 

effects, they were only seen at very high doses (≥4,160 mg/kg/day) and only in 

the presence of maternal toxicity. There were no observed adverse effects for 

both mothers and pups exposed to 1250 mg/kg/day. Based on this information 

the Agency concluded that choline chloride, when used as an inert ingredient, will 

not cause reproductive or developmental toxicity and therefore, does not 

anticipate an increased risk to infants and children. 

In addition to its low toxicity, exposure to choline chloride will be limited. 

Humans are currently exposed to choline on a daily basis through commonly 

consumed foods (both naturally occurring and when added as a nutrient) and 

through the bodies natural ability to synthesize the nutrient. It is unlikely that the 

exposure from choline chloride, when used as an inert ingredient applied preharvest to food commodities, will significantly increase the current concentration 

of choline in foods. Choline chloride is readily biodegradable and because of its 

high water solubility it is expected that most of the inert will be washed from the 

plant prior to consumption. Once in water, its preferred media, it will be broken 

into in a quaternary hydroxyl alkylammonium ion and a chloride ion. 

Similar to humans, choline is a dietary requirement for many animals 

including avian and aquatic species. Based on this information, the 

biodegradability of the chemical, and the available toxicity data, the Agency 

concluded that choline chloride is unlikely to be harmful to mammalian, aquatic, 

and avian organisms. 

In light of the prevalence of choline in the diet, the body’s natural ability to 

synthesis it, the natural occurrence of both choline and chloride, and their low 

toxicity the Agency concluded that there is no increased risk to humans from the 

use of choline chloride as an inert ingredient in pesticide products. Therefore, 

choline chloride has been approved as an inert ingredient in pesticide products 

used on all food commodities under 40 CFR 180.920. 

I. BACKGROUND AND USES

In October 2008 Loveland Products, Inc. submitted a petition to amend 40 

CFR 180.920 by establishing an exemption from the requirement of tolerance for 

the use of choline chloride (Ethanaminium, 2-hydroxy-N, N, N-trimethyl-, chloride; 

CAS Reg. No. 67-48-1) as an inert ingredient in pesticide products when used as 

a solvent on all pre-harvest food commodities. 
4

Choline chloride is a quaternary ammonium salt which dissociates in water 

resulting in a positively charged quaternary hydroxyl alkylammonium ion and a 

negatively charged chloride ion. (OECD, 2004) Choline is an essential 

component of the human diet and acts as a precursor to acetylcholine, 

phospholipids, and the methyl donor betaine. It is important for the structural 

integrity of cell membranes, cholinergic neurotransmission, transmembrane 

signaling, methyl metabolism, and lipid and cholesterol transport and 

metabolism. 

Choline is found naturally in foods (e.g. eggs, liver meats, fungi, soybeans, 

fish, nuts, beans, and wheat germ) in both esterified forms (e.g. phosphocholine, 

glycerophosphocholine, shingomyeline, and phosphatidylchoine) and as free 

choline. Historically, it has been used as a food additive for animal husbandry, in 

plant growth regulator formulations, and as food supplements for humans. 

Choline was officially made an “essential nutrient” in 1998. 

An adequate intake (AI) level for choline has been established by the Food 

and Nutrition Board (FNB) of the National Academy of Science’s Institute of 

Medicine at 550 mg/day for adult men and lactating women. The AI for women is 

425 mg/day and 450 mg/day for pregnant women. This AI was set based on the 

amount necessary to prevent liver abnormalities as indicated by serum levels of 

the liver enzyme alanine aminotransferase (ALT). Daily Upper Intake Levels (UL, 

the highest level of intake that is not likely to cause harm) for choline are: 1 gram 

daily for children 1-8 years, 2 grams for children 9-13 years, 3 grams for children 

14-18 years, and 3.5 grams for adults over 18 years of age”.(National Academy 

of Sciences (NAS), 1998) 

Chloride is a binary compound of chlorine; a salt of hydrochloric acid. 

Chloride is the major extracellular anion and contributes to many body functions 

including the maintenance of osmotic pressure, acid-base balance, muscular 

activity, and the movement of water between fluid compartments. 

II. PHYSICAL AND CHEMICAL PROPERTIES 

Choline chloride is a quaternary ammonium salt which dissociates in water 

resulting in a positively charged quaternary hydroxyl alkylammonium ion and a 

negatively charged chloride ion. Based on its chemical structure choline chloride 

is not expected to undergo hydrolysis. The Mackay Level I V2.11 model indicates 

that for pure choline chloride water is the preferred medium with almost 100% 

distribution. Other compartments such as air, soil, sediment, fish, and aerosol are 

expected to only receive a negligible amount of choline chloride 

(<0.00000005%). 
5

The Mackay model results are consistent with the PCKOCWIN model 

which resulted in a logKoc of 0.37 indicating that choline chloride will not adsorb 

to soil and sediment or suspended solids. According to OECD-criteria, choline 

chloride is readily biodegradable (MITI I-Test: 93% biodegradation within 14 

days). A BOD5 test performed on choline chloride obtained a BOD5/ThOD5 ratio 

of 75% which confirms the biodegradability of choline chloride. (OECD, 2004 

citing MITI, 1992 and BASF AG 1984) Although estimated bioconcentration 

factors (BCF) for choline chloride vary between models, all study results indicate 

that the potential for bioaccumulation is low. 

Using the HENRYWIN model to calculate Henry’s Law Constant resulted 

in 2.06 X10-11 Pa*m3

/mole indicating that choline chloride will not rapidly 

evaporate into the atmosphere (OECD, 2004 citing BASF AG 2003c). In the 

event that choline chloride does enter the atmosphere it is expected to be rapidly 

degraded based on the AOP v1.90 model calculation for OH-radicals (t1/2 of 

approximately 6.9 hours based on a 12 hour day). (OECD, 2004 citing BASF AG 

2004a) 
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Table 1: Summary of physico-chemical properties1

Property Value Remarks and Secondary 

Reference Citations 

Physical state white crystalline solid 

Liquid, colorless, amine-like odor 

Pure choline chloride 

Solution 75% w/w in water; BASF AG 

(2002) 

Physical structure SCCNFP, 2003 

Molecular formula C5H14NO.Cl 

Synonyms Ethanaminium, 2-hydroxy-N, N, N-trimethyl-, 

chloride; Biocoline; Cholinium chloride; 

Hepachloride; Lipotril; Luridin chloride; Paresan; 

Trimethyl (2-hydroxyethyl) ammonium chloride 

Confirmed with CAS Online 

Melting point 247 °C The information corresponds to the pure 

substance; ICSC 0853 (2004) 

Boiling point Not applicable due to decomposition on heating 

Relative density 1.1 g/cm3 at 20°C 70 ± 1% choline chloride. 30% water, less 

than 0.05% impurities measured; BASF 

AG (1974). Data refer to a technical data 

overview, no details of method used and 

year the study was performed is given. 

Further, as the value refers to a solution 

the density of the pure substance may 

differ. 

Viscosity 21 mPa*s at 20°C 70 ± 1% choline chloride. 30% water, less 

than 0.05% impurities measured; BASF 

AG (1974). Data refer to a technical data 

overview, no details of method used and 

year the study was performed is given. 

Vapor pressure 6.57 x 10-8 Pa at 25°C Calculated using MPBPWIN v1.40, refers 

to the pure substance; BASF AG (2003a) 

Water solubility Ca. 650 g/l 50% choline chloride powder; pH=6-7; 

measured; BASF AG (1974); Study 

reliability was not assignable. A calculated 

value for the pure substance of 1000g/l 

was estimated using WSKOW v1.40; 

BASF AG (2003b) 

Partition coefficient 

n-octanol/water (logKow) 

-3.77 at 25°C Solution 75% w/w in water; measured; 

BASF AG (1988a) 

Henry’s law constant 2.06* 10E-11 Pa*m3/mole at 25°C Calculated using HENRYWIN v3.10 (bond 

method), refers to the pure substance; 

BASF AG (2003d) 

logKoc 0.37 Calculated using the PCKOCWIN v1.66 

calculation program (Koc = 2.3), refers to 

the pure substance; BASF AG (2003e) 

 

1

 Source of all information (except *)- OECD SIDS Initial Assessment Report (2004) for-Choline 

Chloride 
7

III. METABOLISM / PHARMACOKINETICS

Choline is a necessary component of the human diet and acts as a 

precursor to the neurotransmitter acetylcholine, phospholipids, and the methyl 

donor betaine. The body requires choline which it obtains through direct ingestion 

of foods/supplements containing choline or through a de novo biosynthesis 

process. According to the OECD SIDS document on choline chloride (2004), 

There is an endogenous pathway for the de novo biosynthesis of the choline moiety via 

the sequential methylation of phosphatidylethanolamine using S-adenosylmethionine as 

the methyl donor. Thus, the demand for dietary choline is modified by metabolic methylexchange relationships between choline and three nutrients: methionine, folate, and 

vitamin B12. 

This de novo process allows the body to produce choline; however, the 

body’s natural synthesis of choline is not sufficient to meet its needs and 

therefore, dietary choline is required. In light of this evidence, choline was 

recognized as an essential nutrient in 1998. Effects have been observed with 

regards to the liver, kidney and brain of choline deficient animals/humans in 

studies where choline has been withheld. (Politizer Shronts, 1997; Zeisel et al., 

1991) 

Once ingested, choline is absorbed from the lumen of the small intestine. 

Prior to adsorption from the gastrointestinal tract some choline is metabolized by 

internal bacteria to form betaine and methylamines. Pancreatic enzymes can 

also breakdown dietary phosphatidylcholine (a.k.a. lecithin) to form free choline. 

Choline is important for the structural integrity of cell membranes, cholinergic 

neurotransmission, transmembrane signaling, methyl metabolism and lipid and 

cholesterol transport and metabolism. 

Chloride is a binary compound of chlorine; a salt of hydrochloric acid. 

Chloride is the major extracellular anion and contributes to many body functions 

including the maintenance of osmotic pressure, acid-base balance, muscular 

activity, and the movement of water between fluid compartments. The World 

Health Organization (WHO) has performed two assessments which determined 

that from a toxicological point of view, there were no concerns for the chloride 

ion. It was considered to be naturally-occurring and a normal participant of 

animal and human metabolism. 

IV. TOXICOLOGY

A. Acute Toxicity 

Oral 

LD50 levels reported in rats for choline chloride show a range from 3150 

and ≥ 6000 mg/kg. Restlessness, hypoactivity, increased frequency of 
8

respiration, convulsions, ruffled coat, staggered gait, and dyspnea were reported. 

Some animals experienced diarrhea and in one study 3 out of 10 rats in the high 

dose group had inflamed lungs at necropsy. (OECD, 2004) Similarly, the LD50

reported for mice was in the range of 3900 to 6000 mg/kg. 

Dermal 

No acute dermal animal studies are available. An in vitro percutaneous 

absorption study was conducted in compliance with GLP under OECD draft 

guideline 428, using human epidermal skin. Liquid scintillation counting was used 

to determine skin absorption of radiolabelled (50 mCi of 1,2-14 C) choline chloride. 

Skin samples were mounted on Franz-type diffusion cells, and [14C]-choline 

chloride was applied to the surface of the skin for 24 hours. Each sample area 

was dosed with a single dose of approximately 10 μl/cm2 of a 5% choline in water 

solution. Samples were evaluated at 1, 2, 6, 12, and 24 hours under occluded 

and non-occluded conditions. 

This study showed that 7.42 μg/cm2 and 13.86 μg/cm2 (1.9 % and 3.43 %) 

of the applied dose was absorbed under occluded and non-occluded conditions 

respectively, with most remaining in the epidermis (5.90μg/cm2 and 10.7 μg/ cm2

) 

and dermis (1.06 μg/cm2 and 2.40 μg/cm2

). Only 0.457 μg/cm2 (0.127 %) and 

0.383 μg/cm2 (0.110 %), of the applied dose penetrated into the receptor fluid for 

occluded and unoccluded cells, respectively. Under the conditions of this study, 

choline chloride is expected to have a low potential for percutaneous absorption 

(SCCNFP, 2003 and SCCP, 2008). 

Inhalation- No valid data available. 

Skin Irritation 

Minor skin irritation (questionable reddening after 24 hour only) was noted 

on the back of 1 of 2 rabbits treated with an aqueous formulation of the test 

substance (70% choline chloride and 30% water). Observations were made at 

24hrs, 2, 3 or 8 days after exposure. This study, however, was an old non-GLP 

(Good Laboratory Practices), non-guideline study whose degree of irritation 

would not be classifiable under the globally harmonized system (GHS). 

Compared to OECD TG 404, this test was harsher due to the longer exposure 

time (20 vs. 4 hrs) and the use of an occlusive rather than a semi-occlusive 

dressing. These factors may lead to an overestimation of the skin irritation 

capabilities of the test substance; therefore, the results are more conservative 

then current studies would indicate. (OECD, 2004 citing BASF AG, 1963) 

 

Eye Irritation 

An eye irritation study performed on choline chloride was conducted 

broadly to OECD test guideline 405, although, it did not comply with GLP due to 
9

the age of the study. One eye of a male and female rabbit were exposed to a 

70% chlorine chloride aqueous solution. The other eye was used as the control. 

After 10 minutes reddening and tear secretions were observed. Slight reddening 

persisted up to three hours after application. Observations were made at 1 and 3 

hours post application and 1 and 8 days. At 1 day post application no effects 

were noted. (OECD, 2004 citing BASF AG, 1963c) 

Skin Sensitization 

No data are available on the sensitization of choline chloride in animals. 

According to the OECD SIDS report (2004) on choline chloride, “the skin 

sensitization potential of chlorine chloride for humans is regarded as negligible”. 

Furthermore, the Scientific Committee on Cosmetic Products and Non-food 

Products Intended for Consumers (SCCNFP) is of the opinion that dermal 

exposure to choline chloride, in rinse off products at 5%, is not anticipated to 

pose any serious risk. (2003) 

B. Repeat Dose Studies 

Although studies have been conducted to evaluate the possible medicinal 

benefits of choline chloride in humans, acceptable repeat dose animal studies 

are limited. Available animal studies have been presented below. 

Male and female Balb/c mice were treated with 200mg/kg/day orally or 

intranasally for 28 days. For orally exposed animals, 200 mg/kg/day was 

administered by oral gavage once daily until day 28. Intranasally exposed 

animals were given 200mg/kg/day in a 50 μl vehicle every other day for 28 days. 

Choline chloride administration by both the oral and intranasal routes of exposure 

did not cause adverse effects with regards to body weight, food and water 

consumption, hematology, clinical biochemistry (Urea, BUN, HDL, TC, ALT, AST, 

and creatinine), or histopathology of various organs (lung, heart, liver, spleen, 

and kidney). Results from intranasal exposure to choline chloride were 

comparable with their respective controls and to other treatment groups 

(intraperitoneal exposure was also assessed). (Mehta, 2009) The NOAEL for oral 

and intranasally administered choline chloride is ≥ 200 mg/kg/day. 

In a limited 72 week feeding study, Fischer 344 rats were given 

approximately 500 mg/kg/day of choline chloride. Animals were observed for 30 

weeks post exposure during which time the test animals and the controls 

received the same untreated diet. Histopathology performed at week 103 was 

restricted to the liver and organs that developed gross abnormalities. There were 

no significant difference between the control and treated group in relation to body 

weights, relative liver weight, or survival rates. The number of neoplastic liver 

nodules, hepatocellular carcinomas, lung tumors, leukemia, or other tumors was 

not increased in treated animals. This study resulted in a NOAEL of 500 

mg/kg/day. (OECD, 2004 citing Shivapurkar, 1986) 
10

C. Neurotoxicity 

Choline is a known precursor to a vital neurotransmitter, acetylcholine. 

The peripheral nervous system uses acetylcholine in skeletal muscle movement, 

as well as in the regulation of smooth muscle and cardiac muscle. In the central 

nervous system acetylcholine is believed to be involved in learning, memory, and 

mood. Choline chloride has been evaluated for its medicinal use in treating 

neurological conditions such as tardive dyskinesia, Alzheimers, Huntington’s 

disease, ataxia, and memory loss in the elderly. (Mohs et al., 1979; Snell et al., 

1980) 

Two studies which evaluated the effects of choline chloride on memory in 

rats showed a positive correlation between choline and memory functions and a 

third study showed no effect. The first study supplemented rats prenatally by 

adding choline to the drinking water of their dams. Another treatment group was 

made deficient of choline during early development by withhold it from the dam’s 

diet. A third group was used as controls. 

After being maintained on a choline-sufficient diet for 120 days postnatally, 

the rats began 12-arm radial maze training. The results of the study (Meck and 

Williams, 1999) indicated: 

Both choline-supplemented and choline-deficient rats performed more accurately than 

control littermates when trials were spaced. These differences in spatial ability did not 

appear to be a function of differential response or cue-use strategies. Cholinesupplemented rats showed little proactive interference when trials were massed; whereas 

control rats demonstrated moderate levels and choline-deficient rats exhibited high levels 

of proactive interference as a function of massed trials. These data suggest that the 

behavioral consequences of early dietary availability of choline may involve the 

modification of the discriminative abilities used to attend to stimuli that demarcate the end 

of one trial and the start of another as well as the capacity for remembering the locations 

that have been visited during a trial. 

A second study utilized a T-maze design to investigate the effect of 

choline supplementation on memory consolidation in young female SpragueDawley rats. One group of rats received choline chloride daily for two weeks and 

a second group was used as a control. In the dark area (DA) of the maze, which 

is naturally preferred by the rat, an electric foot-shock (0.1 mA at 60V) was 

delivered when the rats entered the area. Both the treated and control groups 

showed a preference for the DA and15 minutes after passive avoidance both 

groups avoided entry into the DA. This suggests that both groups had acquired 

short-term memory of the negative stimuli; however, when the test was repeated 

24 hours after training the control group did not avoid entry to the DA, whereas 

the group who received the choline supplements either avoided entry or entered 

after a significantly longer latency period. According to the author, “These results 

suggest that supplementation with choline facilitated the consolidation of short-
11

term memory of the avoidance learning into intermediate long-term memory in 

young rats.” (Gossell-Williams et al., 2006) 

In the third study, male Long-Evans rats were fed diets containing either (i) 

choline chloride 1250 mg/L, (ii) choline chloride 250 mg/L and GD3 24 mg/L, or 

(iii) choline chloride 250 mg/L on postnatal days 5-18. A fourth group was reared 

normally. The study found “all rats were equally proficient at using spatial shortterm memory, regardless of the choline or ganglioside content of the preweaning 

diet”. (Mohs et al., 1979) 

D. Carcinogenicity/Mutagencity 

In vitro studies designed to investigate the ability of choline chloride to 

induce gene mutation in bacteria were negative. Three Ames test were 

conducted with Salmonella typhimurium strains TA 98, 100, 1535, 1537, and/or 

1538, up to 10,000 μg/plate and E. coli WP2 uvrA up to 5,000 μg/plate with and 

without metabolic activation. Although all of the studies were tested up to at least 

the limit dose of 5 mg/plate, two of the tests did not show bacterial toxicity. The 

third study showed a 50% survival at the highest dose tested. (OECD, 2004 

citing Haworth et al., 1984; JETOC, 1997; Litton Bionetics, 1977; and NTP, 

1983). 

NTP reported on three experiments designed to look at choline chlorides 

potential to cause chromosomal aberrations. In one study a small but statistically 

significant increase in simple aberrations was seen at 50 and 500 μg/ml (the 

highest dose tested) in the absence of S9 only. Two reliable Chinese Hamster 

Ovary Cell studies, however, showed that cytotoxicity (50% survival) only 

occurred at choline chloride concentration of 5000 μg/ml. One hundred cells were 

examined per dose and treatment group and S9 from Aroclor induced rat livers 

were used for metabolic activation (OECD, 2004 citing Bloom et al., 1982; 

Galloway et al., 1985; and NTP, 1984). 

 Two parallel sister chromatid exchange assays at two different 

laboratories were conducted on Chinese Hamster Ovary cells at concentrations 

up to 500 and 5000 μg/ml, respectively and gave ambiguous results. According 

to OECD SIDS (2004), 

Cytotoxicity (50% survival) was observed at 5000 μg/ml Metabolic activation was with S9 

from Aroclor induced rate livers. Approximately 1000 chromosomes were examined per 

dose and treatment group. The increase (sporadic and not dose related) in SCEs that 

was observed with metabolic activation in laboratory two was not reproduced in 

laboratory one. Laboratory one showed a weak positive at the top dose without metabolic 

activation, but a comparison with laboratory two was not possible due to insufficient 

numbers of cells analyzed. 

A third study using Chinese hamster ovary cells showed no increase in the 

number of sister chromatid exchanges at concentrations up to 5000 μg/ml with 

and without metabolic activation. (OECD, 2004 citing NTP 1984) Negative results 
12

were also obtained from a gene conversion assay using Saccharomyces 

cerevisiae strain D4 with choline chloride concentration between 12.5 and 50 

mg/ml with and without metabolic activation. (OECD, 2004 citing Litton Bionetics, 

1977). 

The SIDS document concluded that; 

Choline chloride does not have any structural alerts for genotoxicity. It did not produce 

gene mutations, clastogenicity, or DNA damage when tested in vitro. It can be concluded 

from these studies that choline chloride does not have any mutagenic potential. 

An epidemiologic study released in 2007 evaluated the relationship 

between choline and betaine intake and the risk of colorectal adenoma in US 

women enrolled in the Nurses’ Health Study. The study evaluated responses 

from female registered nurses aged 30-55 years who responded to a baseline 

questionnaire on lifestyle and major illnesses in 1976. Every 2 years, a follow-up 

questionnaire was sent to the women to update information regarding diet and 

lifestyle and to ascertain new diagnoses of major illnesses. The study found that 

higher choline intake was associated with an elevated risk of colorectal 

adenoma; however, the investigators stated that: (Cho et al., 2007) 

Our findings do not support an inverse association between choline intake and risk of 

colorectal adenoma. The positive association between choline intake and colorectal 

adenoma that we observed could represent effects of other components in the foods from 

which choline was derived and should be investigated further. 

On the contrary, multiple studies have indicated that choline many have an 

inverse relationship to breast cancer risk. (Xu et al., 2008; Shannon et al., 2005; 

Frazier et al., 2003) 

E. Reproductive/Developmental 

Choline has been shown to have positive effects on development. 

Research suggests that adequate amounts of choline during pregnancy and 

breastfeeding can help ensure healthy fetal brain development. Studies have 

shown that pregnant women consuming a choline deficient diet have a 

significantly higher rate of neural tube and oral cleft defects in their offspring. (Xu 

et al., 2008) Adequate prenatal choline levels may also have long-lasting positive 

effects on cognitive function, including memory. However, sufficient research has 

not been done on the effects of choline on pregnant women and their unborn 

babies. 

A developmental toxicity study exposed NMRI mice to 1250, 4160, 10800, 

or 20000 mg/kg/day every other day from gestation day 1 to 18. In all but the 

lowest group, maternal body weight gain was reduced. Those exposed to ≥4,160 

mg/kg/day showed almost no net weight gain and those exposed to the highest 

tested dose (20,000 mg/kg/day) showed weight loss. Embryonic/fetal lethality 
13

was recorded at 35% and 69% for those tested with 4,160 and 10,800 

mg/kg/day, respectively. No resorptions occurred in the lowest dose group; 

conversely, all fetuses in the highest dose group were resorbed. There was no 

statistically significant, dose related increases in malformations between the 

treated and control groups. (OECD, 2004 citing BASF AG, 1966)

In all but the lowest dosed group, developmental toxicity was observed; 

however, it was not observed in the absence of maternal toxicity. It is important 

to bare in mind that all of the levels tested in this study are much greater than the 

usual limit dose used for a non-toxic compound (i.e. 1000 mg/kg/day). There 

were no observed effects for those both mothers and pups tested with 1250 

mg/kg/day; therefore, the NOAEL for maternal toxicity and developmental toxicity 

is 1250 mg/kg/day. Due to a lack of sufficient pups, a NOEAL for teratogenicity 

was not determined. (OECD, 2004 citing BASF AG 1966) 

Currently, there is a study sponsored by the National Institute of Mental 

Health that will “evaluate the safety and effectiveness of taking choline 

supplements during pregnancy and whether taking choline during pregnancy will 

have an effect on infant development”. The study is expected to be completed in 

March 2010. (NIMH, 2006-2010 proposed) 

F. Endocrine 

 EPA is required under the FFDCA, as amended by FQPA, to develop a 

screening program to determine whether certain substances (including all 

pesticide active and other ingredients) “may have an effect in humans that is 

similar to an effect produced by a naturally-occurring estrogen, or other such 

endocrine effects as the Administrator may designate''. Choline chloride is not a 

known endocrine disruptors nor is it or its metabolites related to any class of 

known endocrine disruptors. 

G. Special Consideration for Infants and Children (FQPA Safety Factor) 

 FFDCA section 408 provides that EPA shall apply an additional tenfold 

margin of exposure (safety) for infants and children in the case of threshold 

effects to account for prenatal and postnatal toxicity and the completeness of the 

data base unless EPA determines that a different margin of exposure (safety) will 

be safe for infants and children. 

 Choline is a natural component of a variety of commonly consumed 

foods (e.g. (per100g food)- eggs (251mg), wheat germ (152 mg), bacon (125 

mg), dried soybeans (116 mg), pork (103 mg), cod (83 mg), beef (80 mg), 

chicken (70 mg), and salmon (65 mg))(USDA, 2004). It has been added as a 

supplement to infant formula in the US for decades (Politizer Shronts, 1997). In 

addition to dietary consumption, choline is made endogenously in the human 

body. 
14

 Choline chloride has been used as a widespread nutrient in animal feed 

since the 1930’s without adverse effects reported on fertility or teratogenicity. 

Although one study in mice did show developmental effects, they were only seen 

at very high doses (≥4,160 mg/kg/day) and only in the presence of maternal 

toxicity. There were no observed adverse effects for both mothers and pups 

exposed to 1250 mg/kg/day. Evidence has shown that choline has beneficial 

properties in regards to proper growth and development and neurological 

function. 

 Exposure to choline chloride not expected to significantly increase the 

pre-existing levels found in commonly eaten foods. Choline chloride residues on 

food is expected to be minimal. Because of its high water solubility most of the 

inert will be washed from the plant prior to consumption. Once in water, it will be 

broken into in a quaternary hydroxyl alkylammonium ion and a chloride ion. 

 Due to the low toxicity of the chemical, the bodies need for choline from 

a dietary source, and the beneficial role choline plays in fetal development; the 

safety factor has been reduced to 1 X. 

V. ENVIRONMENTAL FATE AND DRINKING WATER

Physical chemical properties coupled with modeling indicate that water is 

expected to be the preferred media for choline chloride. The Mackay model 

showed a 100% water distribution and the PCKOCWIN model resulted in a log 

Koc of 0.37, indicating that choline chloride will not adsorb to soil and sediment or 

suspended solids. Once in water choline chloride, a quaternary ammonium salt, 

dissociates resulting in a positively charged quaternary hydroxyl alkylammonium 

ion and a negatively charged chloride ion. (OECD, 2004) Choline chloride is not 

expected to undergo hydrolysis. 

 According to the OECD-criteria, choline chloride is readily biodegradable 

(MITI I-Test: 93% biodegradation within 14 days). A BOD5 test performed on 

choline chloride obtained a BOD5/ThOD5 ratio of 75% which also indicates that 

choline chloride is readily biodegradable. (OECD, 2004 citing MITI, 1992 and 

BASF AG, 1984) Although estimated bioconcentration factors (BCF) for choline 

chloride vary between models, all results indicated that the potential for 

bioaccumulation is low. 

Using the HENRYWIN model to calculate Henry’s Law Constant resulted 

in 2.06 X10-11 Pa*m3

/mole indicating that choline chloride will not rapidly 

evaporate into the atmosphere. (OECD, 2004 citing BASF AG, 2003c) In the 

atmosphere choline chloride is expected to be rapidly degraded based on the 

AOP v1.90 model calculation for OH-radicals (t1/2 of approximately 6.9 hours 

based on a 12 hour day) (OECD, 2004 citing BASF AG, 2004a). 
15

Choline, an essential dietary nutrient, is present in a variety of foods and is 

synthesized by the body. Because of its natural presence in the environment and 

its readily biodegradable nature, choline chloride when used as an inert 

ingredient in pesticide formulations, is not expected to significantly increase the 

levels of naturally occurring choline drinking water or the environment. 

VI. EXPOSURE ASSESSMENT

A. Exposure Profile 

Humans are currently exposed to choline on a daily basis through 

commonly eaten foods (both naturally occurring and when added as a nutrient) 

and through the bodies natural ability to synthesize the nutrient. It is unlikely that 

the exposure from choline chloride, when used as an inert ingredient applied preharvest to food commodities, will significantly increase the natural concentration 

of choline present in foods. Because of its high water solubility it is expected that 

most of the inert will be washed from the plant prior to consumption. Once in 

water, it will be broken into in a quaternary hydroxyl alkylammonium ion and a 

chloride ion. Choline is an essential nutrient and a requirement in many of the 

bodies functions. 

B. Aggregate Exposure 

Section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA) directs 

the Agency to evaluate aggregate exposure from “pesticide chemical residue and 

to other related substances, including dietary exposure under the tolerance and 

all other tolerances in effect for the pesticide chemical residue, and exposure 

from other non-occupational sources”. The expected exposure pathway for 

choline chloride is through the oral and the dermal routes of exposure. 

 Although a method is not require to determine the residues on food 

when an exemption from tolerance is granted it is expected that because of the 

low oral and dermal toxicity, the rapid degradation of the chemical, and the 

natural presence of choline and chloride in the environment, aggregate exposure 

will result in minimal risk to all subpopulation including infants and children. 

Based on the physical and chemical properties, the inhalation route is not a likely 

exposure pathway; therefore, the anticipated risk from inhalation exposure is 

considered minimal. (Cho et al., 2007) 

C. Cumulative Exposure 

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering 

whether to establish, modify, or revoke a tolerance, the Agency consider 

"available information" concerning the cumulative effects of a particular 

pesticide's residues and "other substances that have a common mechanism of 

toxicity." Unlike other pesticides for which EPA has followed a cumulative risk 
16

approach based on a common mechanism of toxicity, EPA has not made a 

common mechanism of toxicity finding as to choline chloride and any other 

substances, and these chemicals do not appear to produce toxic metabolites 

produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that choline chloride has a common mechanism 

of toxicity with other substances. For information regarding EPA's efforts to 

determine which chemicals have a common mechanism of toxicity and to 

evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA's Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to 

have a common mechanism on EPA's website at 

http://www.epa.gov/pesticides/cumulative/

VII. RISK CHARACTERIZATION

Choline chloride is a quaternary ammonium salt which dissociates in water 

resulting in a positively charged quaternary hydroxyl alkylammonium ion and a 

negatively charged chloride ion. (OECD, 2004) Choline is an essential 

component of the human diet and acts as a precursor to acetylcholine, 

phospholipids, and the methyl donor betaine. It is important for the structural 

integrity of cell membranes, cholinergic neurotransmission, transmembrane 

signaling, methyl metabolism, and lipid and cholesterol transport and 

metabolism. 

Choline is found naturally in foods (e.g. eggs, liver meats, fungi, soybeans, 

fish, nuts, beans, and wheat germ) in both esterified forms (e.g. phosphocholine, 

glycerophosphocholine, shingomyeline, and phosphatidylchoine) and as free 

choline. Historically, it has been used as a food additive for animal husbandry, in 

plant growth regulator formulations, and as food supplements for humans. 

Choline was officially made an “essential nutrient” in 1998. The adequate intake 

(AI) level for choline in women is 425 mg/day and 450 mg/day for pregnant 

women. Men and lactating women have a slightly higher AI at 550 mg/day. Daily 

Upper Intake Level for choline is 3.5 grams for adults. (NAS, 1998) Research on 

choline in the diets of the US population using the NHANES, 2003–2004 data 

indicates that many individuals are not getting enough choline, with daily intake 

levels far below the AI. (Jensen et al., 2007) 

Chloride is a binary compound of chlorine; a salt of hydrochloric acid. 

Chloride is the major extracellular anion and contributes to many body functions 

including the maintenance of osmotic pressure, acid-base balance, muscular 

activity, and the movement of water between fluid compartments. The World 

Health Organization has performed two assessments which determined that from 

a toxicological point of view, there were no concerns for the chloride ion. It was 

considered to be naturally-occurring and a normal participant of animal and 

human metabolism. 
17

Choline chloride has demonstrated a low acute oral toxicity with LD50

values for rats ranging from 3150 to ≥ 6000 mg/kg and LD50 for mice in the range 

of 3900 to 6000 mg/kg. Although appropriate animals studies are lacking for 

acute dermal toxicity, an in vitro percutaneous absorption study performed under 

occluded and unoccluded conditions showed that choline chloride is expected to 

have a low potential for percutaneous absorption. Acceptable acute inhalation 

studies are not available. 

Studies were conducted in the early 1960’s to evaluate the eye and skin 

irritation potential of choline chloride. Because their age, the studies were not 

performed under OECD guidelines and therefore the degree of irritation is not 

classifiable under the Globally Harmonized System of Classification and Labeling 

of Chemicals (GHS). Although these results would not be classifiable under 

GHS, it is important to note that only slight transient irritation was observed in the 

skin and eye irritation studies. Choline chloride is not expected to cause skin 

sensitization. 

Repeat dose animal studies on choline chloride are limited. One study 

using male and female Balb/c mice, evaluated the impact of 200 mg/kg/day 

choline chloride given orally or intranasally for 28 days. No adverse effects were 

observed with regards to body weight, food and water consumption, hematology, 

clinical biochemistry (Urea, BUN, HDL, TC, ALT, AST, and creatinine), or 

histopathology of various organs (lung, heart, liver, spleen, and kidney). Results 

from intranasal exposure to choline chloride were comparable with their 

respective controls and to other treatment groups (intraperitoneal exposure was 

also assessed). The NOAEL for oral and intranasally administered choline 

chloride is ≥ 200 mg/kg/day. 

A 72 week feeding study administered 500 mg/kg/day of choline chloride 

to Fischer 344 rats and observed the animals for 30 weeks post exposure during 

which time the test animals and the controls received the same untreated diet. 

There were no significant difference between the control and treated group in 

relation to body weights, relative liver weight, survival rates, and the number of 

neoplastic liver nodules, hepatocellular carcinomas, lung tumors, leukemia, or 

other tumors. This study resulted in a NOAEL of 500 mg/kg. 

Choline is a precursor to the vital neurotransmitter acetylcholine. Studies 

show that choline has beneficial effects on the nervous system and memory. 

Choline is necessary to promote proper development in the fetus and infant and 

prevent cognitive problems. Choline chloride not expected to cause neurotoxicity. 

 Choline chloride is not a known endocrine disruptors nor is it or its 

metabolites related to any class of known endocrine disruptors. Based on the 

results of the in vitro studies the Agency feels that choline chloride is not 

expected to be carcinogenic or mutagenic. 
18

Since the 1930’s choline chloride has been used as a widespread nutrient 

in animal feed without adverse effects reported on fertility or teratogenicity. The 

Food and Drug Administration (FDA) requires choline be added to non-milk 

based infant formulas at a minimum concentration of 7 mg for every 100 

kilocalories (21 CFR 107.100). Although one study did show developmental 

effects, they were only seen at very high doses (≥4,160 mg/kg/day) and only in 

the presence of maternal toxicity. There were no observed adverse effects for 

both mothers and pups exposed to 1250 mg/kg/day. Based on this information 

the Agency does not feel that choline chloride, when used as an inert ingredient, 

will cause reproductive or developmental toxicity and therefore, does not 

anticipate an increased risk to infants and children. 

Choline has demonstrated a beneficial effect on ischemic cardiac 

arrhythmias and preventing liver and renal dysfunction. (Liu, 2008, Canadian 

journal; Zeisel, 2000). Recent studies suggested that cholines anti-inflammatory 

properties may be an effective treatment for asthma, a chronic inflammatory 

disease. (Mehta et al., 2007) Other documented benefits include a reduction in 

DNA hypomethylation and tumor development in the liver. 

In addition to its low toxicity, exposure to choline chloride will be limited. 

The expected exposure pathway is via the oral and the dermal routes. Humans 

are currently exposed to choline on a daily basis through commonly eaten foods 

(both naturally occurring and when added as a nutrient) and through the bodies 

natural ability to synthesize the nutrient. It is unlikely that the exposure from 

choline chloride, when used as an inert ingredient applied pre-harvest to food 

commodities, will significantly increase the natural concentration of choline in 

foods. Choline chloride is readily biodegradable and because of its high water 

solubility it is expected that most of the inert will be washed from the plant prior to 

consumption. Once in water, its preferred media, it will be broken into in a 

quaternary hydroxyl alkylammonium ion and a chloride ion. 

Similar to humans, choline is a dietary requirement for many animals 

including avian and aquatic species. Based on this information, the 

biodegradability of the chemical, and the available toxicity data, the Agency feels 

that choline chloride is unlikely to be harmful to mammalian, aquatic, and avian 

organisms. 

In light of the prevalence of choline in the diet, the body’s natural ability to 

synthesis it, and its low toxicity the Agency does not feel that there is an 

increased risk to humans from the use of choline chloride as an inert ingredient in 

pesticide products. Therefore, choline chloride has been approved as an inert 

ingredient in pesticide products used on all food commodities under 40 CFR 

180.920. 
19

ECOTOXOCITY

Similar to humans, choline is a dietary requirement for many animals 

including avian and aquatic species. Based on this information, the 

biodegradability of the chemical, and the available toxicity data (Table 2), the 

Agency feels that choline chloride is unlikely to be harmful to mammalian, 

aquatic, and avian organisms. 

Acute toxicity testing in fish resulted in a LC50 (96h) for oryzias latipes

and limanda limanda at >100mg/L and >1000mg/L, respectively. For the 

invertebrate Daphnia magna the EC50 (48h) is 349 mg/L and the NOEC (21d) is 

30.2 mg/L. 
20

Table 2: Acute toxicity of choline chloride to aquatic organisms2

 

2

 Table adopted from OECD-SIDS on Choline Chloride (2004) 

Species Method Effect 

Concentration 

(mg/L) 

Remark/Reference 

Acute Toxicity to Fish 

Oryzias latipes 

(freshwater species) 

OECD 203 

(flowthrough 

system) 

LC50 (96h) > 100 

(nominal and 

measured) 

purity of test substance: 100.2 %, 

reliability: 1; MOE Japan (1999a), 

KEY STUDY 

Leuciscus idus 

(freshwater species) 

DIN 38412, part 15, 

static 

LC50 (96h) > 10,000 

(nominal ) 

no symptoms detectable; two tests 

with a) 78 % choline chloride watery 

solution (BASF AG, 1988b) and b) 

50 % choline chloride as powder 

(BASF AG, 1988c) are available, 

non GLP, no analytics (reliability 2) 

Limanda limanda 

(marine species) 

according to OECD 

203, semistatic 

LC50 (96h) > 1,000 

(nominal) 

75 % choline chloride watery 

solution; limit test (only 1,000 mg/L 

tested); ICI (1983) (reliability 2) 

Acute and chronic toxicity to aquatic invertebrates 

Daphnia magna 

(freshwater species) 

OECD 202 (static) EC50 (48h) = 349 mg/l 

(nominal and 

measured) 

purity of test substance: 100.2 %, 

reliability: 1; MOE Japan (1999b), 

KEY STUDY 

Daphnia magna 

(freshwater species) 

Directive 79/831 EEC, 

C2, static 

LC50 (48h) > 500 

(nominal) 

NOEC (48hr) = 125 

78 % choline chloride watery 

solution; non GLP, no analytics 

(reliability 2); BASF AG, 2003g 

Daphnia magna 

(freshwater species) 

according OECD 211 

(renewal system) 

NOEC (21d) = 30.2 

mg/L 

(nominal and 

measured) 

purity of test substance: 100.2 %, 

reliability: 1; MOE Japan (1999c), 

KEY STUDY 

Acute toxicity to aquatic plants e.g. algae 

Pseudokirchneriella 

subcapitata 

(freshwater species) 

OECD 201 ErC50 (72h) > 1,000

(nominal and 

measured), 

72h NOEC (growth 

rate) 

= 32 

purity of test substance: 100.2 %, 

reliability: 1; MOE Japan (1999d), 

KEY STUDY 

Scenedesmus 

subspicatus 

(fresh water) 

DIN 38412, part 9, 

static 

Er(b)C50 (72h) > 

500(nominal), 72h 

NOEC 

(growth rate and 

biomass) >500 

78 % choline chloride watery 

solution; non GLP, no analytics 

(reliability 2); BASF AG, 2003h
21

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