Question number EFSA Q-2003-126
Summary
The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Foods (AFC Panel) has been asked to advise on the safety and bioavailability of d-α-tocopheryl polyethylene glycol-1000 succinate (TPGS) as a source of vitamin E under Commission Directive 2001/15/EC on substances that may be added for specific nutritional purposes in foods for particular nutritional uses. The present opinion deals only with the safety of d-α-tocopheryl polyethylene glycol-1000 succinate as a source of d-α-tocopherol and with the bioavailability of the nutrient from this source, intended to be used in foods for particular nutritional uses. The safety of the nutrient itself, d-α-tocopherol, in terms of amounts that may be consumed, is outside the remit of this Panel.
TPGS is intended to be used in patients (mainly infants and children) with impaired vitamin E absorption due to fat malabsorption. The normal bioavailability of fatsoluble vitamin E depends on fat absorption and requires bile acids and pancreatic enzymes to be present. Conditions where insufficient bile is secreted such as cholestatic liver disease or where insufficient pancreatic enzymes are secreted such as cystic fibrosis lead to impaired vitamin E absorption and if not corrected may lead to neurological disorders. Studies in patients with cholestatic liver disease have shown that TPGS administration can correct impaired vitamin E bioavailability in these patients (at a dose level of 20-25 IU/kg bw/day (51.7 –64.5 mg/kg bw/day).
Studies to address the bioavailability and safety of TPGS have been conducted, both in humans and in animals. The absorption, distribution and excretion of the PEG 1000 moiety of TPGS have been examined in rats in several studies using radiolabelled TPGS. The majority of the radiolabelled material was rapidly eliminated with the faeces (72-85 %) and urine (7-13%) within 24 hours. In teenage children with chronic cholestasis 1.7% of the administered polyethylene glycol 1000 contained in the TPGS was excreted in the urine, compared with 3.0 % in normal adults. This showed that the systemic exposure to PEG 1000 from TPGS was not higher in persons with impaired bile secretion than in normal persons and that it was lower than in rats, the species used in the safety studies on TPGS.
From toxicology studies, an overall no-observed-adverse-effect level (NOAEL) of 1000 mg/kg bw/day can be derived. TPGS is not genotoxic. Limited chronic toxicity and carcinogenicity studies in rats and mice using “PGS 4001” instead of TPGS, which would be expected to provide a higher systemic exposure to PEG, showed no toxic effects at doses higher than the overall NOAEL of 1000 mg/kg bw/day.
The Panel concluded that in the absence of genotoxic effects the safety of TPGS can be assessed on the basis of the overall NOAEL equivalent to 1000 mg TPGS/kg body weight per day, established in a subchronic toxicity study in rats. TPGS is only to be used for food for special medical purposes under medical supervision at estimated intakes varying from 5 mg TPGS /kg bw in teenagers to 13 mg TPGS /kg bw in 1 month old infants. Potential intake would be lower in adults. This provides an adequate margin of safety (ratio between the NOAEL and the intake) compared with the NOAEL of 80 to 200 for infants and young children. The Panel also noted that these estimated intakes to TPGS would correspond to intakes to PEG 1000 at levels equivalent to 3.3 – 8.5 mg/kg bw/day. This is within the range of the group Acceptable Daily Intakes established by the EC Scientific Committee on Food (5 mg/kg bw for PEG 300 – 4000) and the Joint FAO/WHO Expert Committee on Food Additives (10 mg/kg bw for PEGs 200 – 10000).
The Panel noted that under the current Community legislation foods for special medical purposes should be used under medical supervision. The supervising physician will be in a position to weigh up any risks and benefits to the patient and to ensure that the patient receives an adequate dose of vitamin E.
The Panel noted that studies in healthy humans showed that the administration of TPGS, in contrast to fat soluble vitamin E sources, only slightly elevated the plasma α-tocopherol level. Therefore, TPGS is not a useful source of vitamin E in healthy humans with a normal fat absorption.
The Panel therefore concluded that the use of TPGS in foods for special medical purposes is not of safety concern at the anticipated exposure level. However, the Panel noted that it is advised not to apply the TPGS treatment in children with severe impairment of kidney function.
BACKGROUND
The Scientific Committee on Food (SCF) was asked in November 2001 to consider the safety of a number of substances as sources of nutrients for foods for particular nutritional uses (FPNUs). The evaluations could not be completed under the SCF mandate and continuation of this work now falls to the EFSA Scientific Panel on Food Additives, flavourings, processing aids, and materials in contact with food (AFC Panel).
Data on polyethylene glycol (PEG) and on D-alpha-tocopheryl acid succinate (TAS) as source of vitamin E are described in separate opinions (EFSA, 2005; EFSA, 2006), and will not be described in detail in this opinion.
TERMS OF REFERENCE
The Commission asks the European Food Safety Authority (EFSA) to consider the safety and bioavailability of the nutrient source d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) proposed for use in foods for particular nutritional purposes.
Exposure
As TPGS is a synthetic source of vitamin E to be used as FSMP only there will be no contribution from the rest of the diet.
The estimated intake to TPGS has been calculated based on the maximum use level of 0.75 mg vitamin E/100 KJ food permitted according to Directive 1999/21/EC on dietary foods for special medical purposes. On this basis the potential intake will be highest in infants when the energy intake per kg body weight is highest. The potential intakes to TPGS were estimated in male infants, children, and teenagers based on the estimated energy requirement and average body weight as reported by the Scientific Committee for Food (SCF, 1993) and based on the assumption that each gram of TPGS contains 27% d-α-tocopherol (see Table 1).
The estimated potential intake varies from 5 mg TPGS /kg bw/day in teenagers to 13 mg TPGS /kg bw/day in 1 month old infants.
Table 1. Estimated potential exposure to TPGS from use in foods for special medical purposes in infants, children and teenagers.
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Source: Antares, The EFSA Journal (2007) 490, 1-20, Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from the Commission related to D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) in use for food for particular nutritional purposes, Question number EFSA Q-2003-126, Adopted on 17 April 2007
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Nutraceuticals – Efficacy, Safety, And Toxicity
