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Summary of Health Canada’s safety assessment of phosphatidylserine for use as a supplemental ingredient

Abstract

Health Canada's Food Directorate assessed phosphatidylserine for safety, based on publicly available information. The Food Directorate concluded that there was sufficient information to establish conditions under which phosphatidylserine derived from soy, noted phosphatidylserine (soy), could be consumed safely as a supplemental ingredient in foods. Consequently, Health Canada will permit the use of phosphatidylserine (soy) as a supplemental ingredient in food under certain conditions. The conditions are outlined in the Notification of modification.

Introduction

Between 2004 and 2012, after the Natural Health Products Regulations were put in place, Health Canada approved a number of products that had characteristics of both foods and natural health products (NHPs) as NHPs. This inadvertently created confusion among consumers and in 2012, following extensive consultations, Health Canada began regulating products that look like foods and are consumed as foods, as foods, noting that 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 products, on a case-by-case basis and under specific conditions, while regulations were being developed for these types of products (that is, supplemented foods containing supplemental ingredients). 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 phosphatidylserine, were listed in Appendix 2 of Health Canada's Category Specific Guidance for Temporary Marketing Authorization: Supplemented Food, for further assessment to determine conditions (for example, 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 were obtained 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 decision to allow the use of phosphatidylserine (soy) as a supplemental ingredient.

Approach

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 labels to mitigate risks, when unlimited consumption may not be safe. Based on the Food Directorate's safety assessment approach, only limited cautionary labelling is considered appropriate for foods containing supplemental ingredients (such as phosphatidylserine). 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 (that is, safe) levels. Ingredients that require more extensive cautionary labelling (such as 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.

Safety assessment

The safety assessment included a review of the available information on phosphatidylserine for the purposes of evaluating toxicological, nutritional and allergenicity endpoints. Based on this information, and in consideration of the background dietary exposures, a recommended maximum daily intake (RMDI) was derived for the use of phosphatidylserine (soy) as a supplemental ingredient.

Characterization/Standardization of the supplemental ingredient

Most commercially available phosphatidylserine products for food applications are derived from soy through an enzymatic reaction catalyzed by phospholipase D (PLD) with lecithin and serine as starting materials. Phosphatidylserine for food applications is manufactured and marketed in powder and fluid forms, at different concentrations, ranging from 10% to 90%. This safety assessment does not apply to phosphatidylserine derived from sources other than soy.

Dietary exposure

Phosphatidylserine is naturally present in a wide variety of foods; however, the content and composition of naturally occurring phosphatidylserine can vary greatly based on the source (for example, plant or animal), and processing. Foods with relatively high amounts of naturally occurring phosphatidylserine include fish (mackerel, herring, eel, and tuna), poultry, and other meats. Phosphatidylserine is also naturally present in vegetables, legumes and fruit juices but at levels too low to be considered as dietary sources of phosphatidylserine of any relevance. The mean daily dietary intake of phosphatidylserine was estimated to be 228 mg per day (Degusa Food Ingredients GmbH, 2006). This value was determined using the United States Department of Agriculture's consumption data from the 1994-96, 1998 Continuing Survey of Food Intakes by Individuals (CSFII), and known phosphatidylserine levels from food composition and nutrition tables; equivalent Canadian data is not available but would likely be similar.

Requirements for complying with the Supplemented Food 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 phosphatidylserine (soy) itself, as described in this document.

Toxicological safety

Absorption, distribution, metabolism and excretion studies

Before being absorbed in the intestine, phosphatidylserine is hydrolyzed by pancreatic enzymes (such as phospholipase A2) in the intestinal lumen, and then taken up by the enterocytes as free fatty acids and lyso-phosphatidylserine. In the mucosal cells, both free fatty acids and lyso-phosphatidylserine can be re-esterified into phosphatidylserine, or alternatively the free fatty acids can be esterified into triacylglycerol.

Studies in animals showed that most of the ingested phosphatidylserine is converted into other phospholipids (but mainly to phosphatidylethanolamine) due to the high phosphatidylserine decarboxylase activity within mucosal cells (Bruni et al., 1992). Although extensively metabolized, small fractions of oral phosphatidylserine reach the systemic circulation and increase the phosphatidylserine content of target organs/tissues. Animal studies have shown that phosphatidylserine reaches the brain tissue following intravenous or oral administration (Babenko and Semenova, 2011).

The majority of ingested phosphatidylserine is excreted in the faeces as lyso-phosphatidylserine, with a smaller amount excreted in the urine.

Toxicology studies

Repeated dose, reproductive, developmental, and genotoxicity endpoints were considered to determine the potential toxicity of phosphatidylserine. No toxicity studies of phosphatidylserine (soy) were identified. Instead, identified toxicity studies tested bovine-derived phosphatidylserine (B-PS) or fish-derived phosphatidylserine (F-PS). Results are summarized below (N.B. the toxicological studies cited below are not exhaustive, but rather represent the studies that are critical to the conclusions of the safety assessment).

No adverse effects were observed in rats exposed to B-PS by oral gavage at doses up to 1000 mg/kg bw per day for 26 weeks, or in dogs exposed to B-PS by oral gavage at doses up to 1000 mg/kg bw per day for 1 year (Heywood et al., 1987).

No adverse effects on development (for example, on litter size, on litter weights, or abnormalities in pups) were observed after pregnant rats were exposed to B-PS by oral gavage at doses up to 200 mg/kg bw per day during gestation days (GD) 6 to 15, or after pregnant rabbits were exposed to B-PS by oral gavage at doses up to 450 mg/kg bw per day during GD 6 to 18 (Heywood et al., 1987).

No adverse effects (for example, on reproduction or development of pups) were observed after rats were exposed to F-PS in the diet at doses up to the equivalent of 1480 mg/kg bw per day four weeks before mating, during mating, gestation and lactation until postnatal day (PND) 21. After weaning on PND21, the pups received the same diets as their parents for another 13 weeks, followed by a 4-week recovery period. This 13-week phase of the study followed Organisation for Economic Co-operation and Development (OECD) test guidelines. The only potentially significant effect observed was an increased incidence of minimal to mild renal mineralization in female rats. While the biological significance of this effect is uncertain, given that there were no inflammatory or degenerative changes, cellular necrosis, or any other morphological, biochemical or physiological effects in the kidneys (Lifshitz et al., 2015), the no observed adverse effect level (NOAEL) of 960 mg/kg bw per day (mid-dose) for this effect was chosen as a conservative toxicological point of departure.

No mutagenicity or clastogenicity was observed in several in vitro studies, as well as one in vivo study, testing B-PS or F-PS (Heywood et al., 1987; Lifshitz et al., 2015). The genotoxicity studies with F-PS (that is, in vitro bacterial reverse mutation and micronuclei assays) followed OECD guidelines (Lifshitz et al., 2015).

Clinical studies

Clinical studies were reviewed for evidence of toxicity. Two double-blinded, placebo-controlled clinical studies, which included safety parameters (for example, blood/urine measures), as well as reporting of adverse events, were identified for phosphatidylserine (soy). Results are summarized below (N.B. the clinical studies cited below are not exhaustive, but rather represent the studies that are critical to the conclusions of the safety assessment of phosphatidylserine (soy)).

Elderly female and male volunteers with mild memory impairment were exposed orally to 0 (placebo), 100 or 300 mg per day of phosphatidylserine (soy) for 6 months in a randomized, double-blind, placebo-controlled, parallel-group trial. No significant differences were observed between groups for adverse events, vital signs, biochemical or hematological parameters (Kato-Kataoka et al., 2010).

Elderly male and female volunteers with age-associated memory impairment were exposed orally to 0 (placebo), 300 or 600 mg per day of phosphatidylserine (soy) for 12 weeks in a randomized, double-blind, placebo-controlled, parallel-group trial. No significant differences were observed between groups for adverse events, vital signs, biochemical or hematological parameters (Jorissen et al., 2002).

Recommended Maximum Daily Intake (RMDI) derivation

In consideration of the available data, an RMDI of 300 mg/day for phosphatidylserine (soy) was established. This was based on two double-blinded, placebo-controlled, clinical studies, which included measured safety parameters, and used phosphatidylserine (soy) as the test material. This was established in combination with supporting toxicity studies, which tested phosphatidylserine (non-soy).

Additional support for safety was provided by OECD guideline-compliant genotoxicity and repeated-dose toxicity studies of phosphatidylserine (non-soy). No adverse effects were observed in a well-conducted toxicity study of F-PS up to the equivalent of 960 mg/kg bw per day, which was considered to be the NOAEL. Applying an uncertainty factor of 100 for inter- and intra-species differences, results in a value of 672 mg per dayFootnote 1. Subtracting the average background dietary exposure of 228 mg per day would result in an RMDI of approximately 400 mg per day phosphatidylserine (non-soy). Due to the shared molecular structure (aside from the variation in the fatty acid side chains) between the F-PS toxicity test article and phosphatidylserine (soy), the RMDI derived from the toxicity studies provides additional support for the safety of phosphatidylserine (soy).

It is noted that no adverse effects were observed in one of the clinical studies of phosphatidylserine (soy) up to 600 mg per day for 12 weeks in a sensitive subpopulation (that is, elderly). Subtracting the average background dietary exposure of 228 mg per day would result in an RMDI of approximately 400 mg per day. However, the slightly lower level of 300 mg phosphatidylserine (soy) per day was chosen, given that this level was included as a dose in both of the aforementioned clinical studies, including the study with a longer duration of 6 months.

Allergenicity

Soy is a priority allergen; however, allergenic concerns are linked almost exclusively to proteins. Phosphatidylserine derived from soy is expected to contain no or very low levels of soy proteins, suggesting a low potential for allergenic risk. However, soy will be included as part of the ingredient name on the label of the supplemented food product (that is, phosphatidylserine (soy)), therefore, soy-allergic individuals will be adequately informed of the potential presence of soy protein.

Nutritional safety

Overall, no nutritional safety concerns were identified.

There are no Dietary Reference Intakes set by the National Academies of Sciences, Engineering and Medicine (NASEM) specifically for glycerophospholipids, including phosphatidylserine.

Phosphatidylserine is mainly metabolized to triacylglycerol, as well as other phospholipids, and thus could supply energy to the body through the oxidation of the conjugated fatty acids. However, the daily addition of 300 mg of phosphatidylserine (soy) to the diet would not contribute significantly to the energy intake.

Serine is a non-essential amino acid, which means it can be synthesized by the body. Evidence suggests that following ingestion of phosphatidylserine, most of the serine moiety would not be available or used directly to increase the levels of free serine in the body (Toffano et al., 1987).

Phosphatidylserine (soy) generally contains five types of fatty acids: palmitic, stearic, oleic, linoleic (an omega-6 fatty acid), and alpha-linolenic (an omega-3 fatty acid), with linoleic being the most abundant (> 60%). These fatty acids are commonly found in the diet from vegetable and/or animal fat sources. No Tolerable Upper Intake Level (UL) has been set by NASEM for cis polyunsaturated (omega-3 and omega-6) fatty acids or total fat; therefore, the contribution of phosphatidylserine (soy) to the individual intake of fatty acids is not a concern.

Conclusion and decision

Health Canada's Food Directorate determined there to be sufficient information to establish conditions under which phosphatidylserine (soy) would be safe for use as a supplemental ingredient. Consequently, Health Canada will permit the use of phosphatidylserine (soy) as a supplemental ingredient under certain conditions. These conditions are outlined in Health Canada’s Notice of modification.

Supplemental ingredient submissions for phosphatidylserine

To propose future, additional changes to the conditions of use for phosphatidylserine (soy) as a supplemental ingredient, stakeholders can submit a pre-market 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 (smiu-ugdi@hc-sc.gc.ca).

The information set out below is recommended to be included in the submission, if relevant to the nature of the request.

For requests to include phosphatidylserine formulations outside of the current phosphatidylserine (soy) characterization, the submission must characterize in detail the phosphatidylserine that is requested for supplemental use. It must also clearly demonstrate that the safety information in the submission applies to the requested phosphatidylserine. For example, the submission must explain why the results of toxicity testing of a particular phosphatidylserine formulation apply to the phosphatidylserine to be used as a supplemental ingredient.

In general, any submitted safety information should be of good quality (for example, GLP/GCP and OECD compliant), and contain full study reports, not summaries. The reports should provide clear, detailed characterization of the phosphatidylserine test material, and a full description of the study design, including methods, the type and number of animals treated, the doses administered, and the toxicological endpoints measured. Studies should also provide a detailed documentation of the test results. Similarly, the submission of clinical studies should provide fulsome details of the study design, providing toxicologically-focused endpoints that contribute information to the assessment of the safety of the ingredient.

Future requests to modify phosphatidylserine (soy) conditions, such as the maximum serving amount, RMDI, or labelling, may require addressing data gaps that were identified in the current toxicological assessment and the nutritional assessments, such as the following:

Toxicological data gaps/uncertainties

  1. Reproductive and developmental toxicity

Nutritional data gaps/uncertainties

  1. Information that would provide adequate evidence that phosphatidylserine would not affect digestion or absorption of other nutrients, especially in the intestines, and/or information that it would not pose nutritional safety concerns if foods supplemented with phosphatidylserine were to be consumed frequently over a long period of time in different food matrices.

Health Canada may ask for additional data or other information related to the safety of phosphatidylserine for use as a supplemental ingredient after reviewing the above information.

References

Footnotes

Footnote 1

Daily intake of phosphatidylserine in the toxicity study = 960 mg/kg bw per day ÷ 100 total uncertainty = 9.6 mg/kg bw per day × 70 kg (the body weight of a healthy adult) = 672 mg per day.

Return to footnote 1 referrer

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