Summary of Health Canada’s safety assessment of L-alpha-glycerylphosphorylcholine for use as a supplemental ingredient
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- Safety assessment
- Conclusion and decision
- Supplemental ingredient submissions for AGPC
Health Canada's Food Directorate assessed L-alpha-glycerylphosphorylcholine (AGPC) for safety as a supplemental ingredient in foods, based on publicly available information. The Food Directorate concluded that AGPC can be considered a source of supplemental choline and will thus be subject to the conditions of use for choline set out in the List of Permitted Supplemental Ingredients. Consequently, Health Canada plans to allow the use of AGPC as a supplemental ingredient in foods under certain conditions. The conditions are outlined in the Notice of Proposal.
Between 2004 and 2012, after the Natural Health Products Regulations were put in place, Health Canada approved a number of products as natural health products (NHPs) that had characteristics of both foods and NHPs. This inadvertently created confusion among consumers. Therefore, following extensive consultations, Health Canada began in 2012 the transition of products that look like foods and are consumed as foods, based on their overall representation, to the food regulatory framework. This would allow Canadians to make more informed choices due to consistent nutrition information and labelling requirements.
During the transition between regulatory frameworks, certain herbal and non-herbal ingredients in these products were identified as not having a history of safe food use or were being used in these products at a level that was inconsistent with food use. As an interim measure, Health Canada used Temporary Marketing Authorizations (TMAs) to permit the sale of foods containing such supplemental ingredients, on a case-by-case basis and under specific conditions, while regulations were being developed for these types of products. Supplemental ingredients have historically been marketed as providing specific physiological or generally beneficial health effects. However, they can pose health risks if overconsumed by the general population, or if consumed by certain vulnerable populations.
Some of these ingredients, including AGPC (also known as alpha GPC or choline alfoscerate), were listed on Appendix 2 of Health Canada's Category Specific Guidance for Temporary Marketing Authorization: Supplemented Food, for further assessment to determine conditions (e.g., use levels, specifications, and/or labelling statements), if any, under which they would be safe for use as supplemental ingredients.
The scientific information/studies that serve as the basis of the safety assessments of Appendix 2 ingredients were obtained by Health Canada from a search of publicly available primary literature, web searches on specific topics, and citations noted in other articles.
This document summarizes the safety considerations that informed Health Canada's proposal to allow the use of AGPC as a supplemental ingredient.
The acceptability of a food ingredient typically considers its safety for the general population, over a lifetime of exposure with no limits on consumption; however, the safety assessment approach for supplemental ingredients gave further consideration to the potential use of cautionary labelling. Based on the Food Directorate's safety assessment approach, only limited cautionary labelling is considered appropriate for foods containing supplemental ingredients (such as AGPC). This labelling is designed to mitigate potential risk(s) identified for sensitive subpopulations, and to help ensure that the intake of the supplemental ingredient, through the diet, remains within acceptable (i.e., safe) levels. Ingredients that require more extensive cautionary labelling (e.g., contraindications) to protect the consumer are not considered appropriate for food use. More information about labelling of supplemented foods is available in the Guidance Document: Supplemented Foods Regulations July 2022.
The safety assessment included a review of the available information on AGPC for the purposes of evaluating toxicological, nutritional and allergenicity endpoints. AGPC is an esterified form of choline and, once consumed, evidence demonstrates that it is converted to choline. Therefore, AGPC will be subject to the conditions of use for choline set out in the List of Permitted Supplemental Ingredients, which is a document incorporated by reference into the Food and Drug Regulations.
Characterization/Standardization of the ingredient
AGPC (C8-H20-NO6-P) has a molecular weight of 257.221 g/mol. AGPC can be synthesized from natural phosphatidylcholine sources (e.g., soy, sunflower) through processes such as chemical synthesis, chemical hydrolysis, chemical alcoholysis and enzymatic hydrolysis. Methods of purification include solvent extraction, precipitation, recrystallization, and resin column chromatography.
The Food Directorate has estimated choline intakes from food using data from the Canadian Community Health Survey (CCHS) 2015. Dietary food intake estimates for total choline intake at the 95th percentile in Canadians are as follows: 369 mg/day for 4- to 8-year-olds, 356-425 mg/day for 9- to 13-year-olds, 404-659 mg/day for 14- to 18-year-olds, and 396-721 mg/day for adults. Choline supplement use was considered minor. CCHS 2015 data indicate the prevalence of choline supplement use is less than 10%, and the mean, all person, daily choline supplement intake is below 1 mg/day for all dietary reference intake (DRI) life stage groups. Further, 2017 Neilson data indicate that top selling multivitamin and mineral supplements in Canada for children and adults do not contain choline.
AGPC is found in a variety of foods including dairy products, meats, fruits, vegetables, and grains; and thus, is commonly consumed. Dietary intake estimates for AGPC are available for some ethnic/racial subpopulations (e.g., 188,147 Caucasians, Japanese Americans and Native Hawaiians living in Hawaii and African Americans and Latinos living in Los Angeles (Yonemori et al., 2013), 125 healthy women 18-40 years of age from the staff and students of a university in New Zealand (Mygind et al., 2013), 920 men and 1040 women, mostly Caucasian and living in Massachusetts, who were participants of the Framingham Offspring Study (Cho et al., 2006), and 598 pregnant or lactating women, primarily Caucasian, living in Alberta who were participants of the Alberta Pregnancy Outcomes and Nutrition study (Lewis et al., 2014)). These data from sufficiently large and diverse samples of people to be representative of Canadian consumers indicate that 16-19% of ingested choline is AGPC.
Requirements for complying with the Supplemented Foods Regulations
As with any food, the onus is on the food manufacturer or distributor to ensure that a food offered for sale in Canada complies with all regulatory provisions, including but not limited to requirements under the Food and Drugs Act (FDA) and the Safe Food for Canadians Act (SFCA), and the Regulations associated with these Acts. This includes, for example, ensuring compliance with food labelling requirements, provisions for the use of food additives and the general prohibitions in section 4 of the FDA, which prohibits selling a food that contains a poisonous or harmful substance. More information on other requirements for Supplemented Foods is available in the Guidance Document: Supplemented Foods Regulations. These requirements are independent from the safety review of AGPC itself, as described in this document.
The National Academies of Science, Engineering and Medicine (NASEM), formerly the Institute of Medicine (IOM), recognizes choline as an essential nutrient that is found in foods and is consumed as free choline or choline esters, including phosphatidylcholine, phosphocholine, sphingomyelin, and glycerophosphocholine. Glycerophosphocholine and choline alfoscerate (the International Nonproprietary Name as a pharmaceutical ingredient) have the same molecular formula as AGPC and are listed as synonyms for AGPC by the National Center for Biotechnology (2022).
Studies in animals have shown that, upon ingestion, AGPC is cleaved in the gut into choline and glycerol-1-phosphate (Abbiati et al., 1993). The choline enters the portal circulation and can be used for synthesizing acetylcholine, whereas glycerol-1-phosphate, after phosphorylation, enters the phospholipid pool. The main circulating metabolite after ingestion is choline; intact AGPC was not detected in the plasma. Both the choline and glycerol-1-phosphate are widely distributed throughout the body, with higher concentrations found in the liver, kidney, spleen, and lung. A minor amount of AGPC ingested orally is excreted in urine and feces. AGPC oral administration results in an increase of plasma choline levels and acetylcholine levels in neurons of the hippocampus and cerebral cortex (Abbiati et al., 1993, Traini et al., 2013; Govoni et al., 1992).
AGPC has been shown to have a bell-shaped dose effect relationship in both in vitro (e.g., rat brain protein kinase C activity (Govoni et al., 1993)) and behavioural studies (e.g., antagonism of scopolamine-induced amnesia (Lopez et al. (1991)) and antagonism of passive avoidance behaviour (Govoni et al., 1992). It has been hypothesized that the higher levels of AGPC lead to excess acetylcholine synthesis, triggering homeostatic mechanisms such as receptor desensitization or activation of presynaptic inhibitory receptors (Govoni et al., 1993). This hypothesis is supported by in vivo studies (Missale et al., 1992) and suggests that homeostatic mechanisms provide some protection against higher levels of intake.
The Institute of Medicine (IOM) (1998) has determined dietary reference intakes for total choline, including phosphocholine, glycerophosphocholine (which is a synonym of AGPC), phosphatidylcholine, and sphingomyelin. The adequate intake (AI) for choline is 550 mg/day for adult males, 425 mg/day for adult females, 550 mg/day for males 14 to 18 years, 400 mg/day for females 14 to 18 years, 375 mg/day for 9- to 13-year-olds, and 250 mg/day for children 4 to 8 years based on the amount of choline required to prevent liver damage and fatty liver. These levels are equivalent to 7 mg/kg bw/day for men and women. Canadian exposure estimates (based on CCHS 2015) indicate mean intakes of choline from food and supplement intake are below the AI for all DRI life stage groups.
The tolerable upper limit (UL) for choline derived by the IOM (1998) is 3500 mg/day for adults based on adverse effects (e.g., hypotension, nausea, and diarrhea) observed during clinical treatment trials. A UL for children aged 1 to 8 years (1000 mg/day), 9 to 13 years (2000 mg/day), and 14 to 18 years (3000 mg/day) has also been derived by scaling according to reference body weight. Canadian exposure estimates (based on 95th percentile intakes from CCHS 2015) for choline from food and supplement use indicate that none of the population exceeds the UL for choline.
Clinical studies using orally consumed AGPC have been conducted generally on populations with pre-existing medical conditions (e.g., Alzheimer's, dementia, and stroke) as part of a therapeutic treatment regimen. The doses used were up to 1200 mg/day (Ban et al., 1991; Moreno, 2003; Sangiorgo et al., 1994). No data was available using oral doses greater than 1200 mg/day in humans, or at any dose in pregnant and breastfeeding women, children, or adolescents.
AGPC once ingested is converted to choline and there is no indication that AGPC represents any additional risk compared to any other sources of choline. There are no anticipated risks from consuming AGPC in excess of 1200 mg/day, based on studies testing lower doses.
Choline is already a supplemental ingredient set out in the List of permitted supplemental ingredients, with a maximum amount per serving of 1171 mg in supplemented foods other than caffeinated energy drinks (CEDs) and a maximum amount per serving of 478 mg in CEDs. Since AGPC is an esterified form of choline and once consumed is converted to choline, it is considered a source of choline. As such, it is subject to the conditions of use for choline set out in the List and the amount of choline provided by AGPC (1 mg AGPC = 0.4 mg choline) needs to be taken into account as contributing to the maximum amount of choline per serving and the threshold levels for cautionary labelling.
The amount of choline provided by AGPC will be declared as choline in the Supplemented Food Facts table. The declaration will include all sources of choline (e.g., AGPC, other supplemental sources of choline, naturally occurring choline).
The current listing for choline in the List of permitted supplemental ingredients states that "If the amount of choline declared on the label is more than 234 mg per serving, the following additional cautionary statements are required: "Do not [eat/drink] on the same day as any other supplemented foods or supplements with [the same supplemental ingredients/(name specific ingredients)]". This statement is intended to mitigate the risk of over consumption of choline from other supplemented foods or supplements. However, supplements generally do not list AGPC as choline, therefore it would be difficult for a consumer to determine that a supplement with AGPC should not be consumed with a supplemented food that contains more than 234 mg choline per serving. To mitigate this risk the required cautionary statement will be revised to: "Do not [eat/drink] on the same day as any other supplemented foods or supplements with choline, including L-alpha-glycerylphosphorylcholine (alpha GPC)".
The established maximum levels and conditions of use for choline in supplemented foods were set using a risk-based approach to help ensure that their addition does not contribute to excessive intakes. Details on the approach for setting maximum amounts for vitamin and minerals in supplemented foods can be found in Appendix 4 of the Guidance document: Supplemented Foods Regulations.
The relevant toxicological data from in vitro assays, animal studies, and adverse events/tolerance information from human clinical trials were used to characterize the toxicological safety of AGPC for use as a supplemental ingredient.
Animal studies that were identified for AGPC evaluated acute, subchronic, and genotoxicity endpoints (Brownawell et al., 2011). Studies were conducted in accordance with the applicable OECD Guidelines, except where noted. No chronic/carcinogenicity or reproductive/developmental studies were identified for AGPC in the available literature.
AGPC elicited low acute toxicity. Rats and mice had an LD50 ≥ 10 g/kg bw and Beagle dogs had an LD50 > 3 g/kg bw.
In a sub-chronic (26-week) toxicity study of AGPC, Sprague-Dawley rats were administered oral doses (via gavage) of 0, 100, 300 or 1000 mg/kg bw per day (n = 18 per sex per group). No treatment-related differences were detected for necropsy, histology, urinalysis, or hematology (at any dose). At the end of the study, the high-dose group demonstrated lower body weight, which was statistically significant when compared to the control group. The lower body weight was correlated with lower food consumption and returned to normal after a recovery period. Additionally, some clinical chemistry parameters measured (i.e., plasma triglycerides, bilirubin, alkaline phosphatase) were significantly lower, but were within published reference ranges; decreases in these values are not typically associated with organ damage (supported by the absence of histopathological changes).
An additional effect observed at the maximum dose of 1000 mg/kg bw per day in the aforementioned study, was a reduction in spontaneous motor activity and reactivity to stimulation within 1-2 hours of dosing, which continued for 3-5 hours. These parameters were not quantified, and it was noted that there was considerable variability between animals. This was a transient, subjective effect following gavage dosing, and was likely related directly to bolus dosing (given that the animals quickly recovered).
In a short-term (26-week) toxicity study of AGPC, Beagle dogs were administered oral doses (via gavage) of 0, 75, 150 or 300 mg/kg bw per day; this study did not meet OECD Guidelines.Footnote 1 At the highest dose, this study resulted in similar observations to the sub-chronic rat study, and no toxicological adverse effects were demonstrated.
Based on the well-conducted sub-chronic oral toxicity study in rats, the NOAEL is considered to be the highest dose tested, 1000 mg AGPC/kg bw per day.
AGPC did not demonstrate genotoxic activity. AGPC was not mutagenic in an Ames assay and was not clastogenic in an in vivo mouse micronucleus assay (exposure via subcutaneous injection).
Three clinical studies (two open trials and one double-blinded, placebo-controlled), where adverse effects were monitored, have shown that AGPC is well tolerated at the recommended therapeutic dose of 1200 mg per day (up to 6 months), with a low incidence of adverse events (up to 8%) (Ban et al., 1991; Moreno, 2003; Sangiorgo et al., 1994). Side effects included agitation, heartburn, insomnia, nausea, headache, fever, and hypotension; these effects were temporary, and did not require discontinuation of treatment. Some of the side effects (headaches, nausea, or dizziness) were also reported by the placebo group in the double-blinded, placebo-controlled study. No serious side effects or toxicities were observed.
Allergenic concerns are linked almost exclusively to proteins. Therefore, since AGPC does not contain any protein, it is not expected to trigger an immune response.
Conclusion and decision
Since AGPC is an esterified form of choline, and once consumed is converted to choline, it is considered a source of choline. There is no indication that AGPC represents any additional risk compared to any other sources of choline. There is also a lack of toxicological concern for AGPC as indicated by the animal toxicity data and human clinical studies.
Based on the review of AGPC, Health Canada's Food Directorate has determined there to be sufficient information to establish conditions under which AGPC would be safe for use as a source of supplemental choline in foods. Consequently, Health Canada proposes to allow the use of AGPC by amending the choline entry in the List of permitted supplemental ingredients as outlined in Health Canada's Notice of proposal.
Supplemental ingredient submissions for AGPC
To propose future, additional changes to the conditions of use for AGPC as a source of supplemental choline, stakeholders can submit a premarket request to the Food Directorate, as described in the Guidance Document: Supplemented Foods Regulations. Manufacturers and distributors are encouraged to request a pre-submission consultation with the Food Directorate to seek additional guidance so that a complete submission can be filed at the outset, potentially reducing the number of requests to the applicant for clarification or additional information or preventing the submission from being rejected for incompleteness. Pre-submission consultations on supplemental ingredients may be arranged by contacting the Submission Management and Information Unit (firstname.lastname@example.org).
The information set out below is recommended to be included in the submission, if relevant to the nature of the request.
Updated information regarding the safe daily amount for choline (e.g., revisions to the Tolerable Upper Intake Levels established by National Academies of Science, Engineering and Medicine (NASEM), or from alternative scientific sources if determined to be more appropriate), and/or updated Canadian choline intake data from food and supplements (e.g., Canadian Community Health Survey).
Health Canada may ask for additional data or other information related to the safety of AGPC for use in supplemented foods after reviewing the above information.
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