Opinion of the Scientific Panel AFC

Adopted on 17 April 2007. (Question Nº EFSA-Q-2003-126).

Related to D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) in use for food for particular nutritional purposes

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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-a-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-a-tocopheryl polyethylene glycol-1000 succinate as a source of d-a-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-a-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 fat-soluble 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 “TPGS-400[1]” 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.

Opinion

Summary

[1] In this opinion, the term “TPGS-400” is used for d-a-Tocopheryl polyethylene glycol-400 succinate.

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Opinion of the Scientific Panel AFC

Adopted on 17 April 2007. (Question Nº EFSA-Q-2005-044).

Related to Calcium ascorbate with a content of threonate for use as a source of vitamin C in food supplements

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The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food has been asked to advice on the safety and bioavailability of the substance calcium
ascorbate with a content of threonate, when used as a source of vitamin C in food supplements.

The present opinion deals only with the safety and bioavailability of the particular source of vitamin C, calcium ascorbate with a content of threonate, to be used as a nutritional substance in
food supplements. The safety of vitamin C itself, in terms of the amounts that may be consumed, is outside the remit of this Panel and has previously been evaluated by EFSA’s Scientific
Panel on Dietetic Products, Nutrition and Allergies and by the Scientific Committee for Food (SCF).

Calcium ascorbate with a content of threonate is a product consisting of the calcium salt of L-ascorbic acid (vitamin C) and less than 2% of L-threonic acid along with calcium carbonate and
water.

The bioavailability of vitamin C from calcium ascorbate with a content of threonate is comparable to that of ascorbic acid.

The toxicity studies and mutagenicity tests with calcium ascorbate with a content of threonate, with calcium threonate or L-threonic acid, hemicalcium salt indicate that the compounds are of
low toxicity and are not mutagenic. Data on carcinogenicity, long-term studies, reproductive and developmental toxicity of calcium ascorbate with a content of threonate were not presented. Such
toxicity studies are not needed in the light of the dissociation of calcium ascorbate with a content of threonate to substances which are physiologically present in the body (ascorbate,
threonate, calcium) and considering that the safety of ascorbic acid (and its calcium and sodium salts), and calcium was previously evaluated.

The intended conditions of use of calcium ascorbate with a content of threonate correspond to those of other approved sources of vitamin C. The additional exposure to calcium and threonate
through use of supplements with calcium ascorbate with a content of threonate does not represent a cause of safety concern.

The Panel noted that threonate is a normal metabolite in the body and concluded that the use of calcium ascorbate containing up to 2% threonate as a source of vitamin C in food supplements is
not of safety concern.

Opinion

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