Download Opinion of the Scientific Panel on Food - EFSA

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
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 glycol1000 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
© European Food Safety Authority, 2007
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EFSA Journal (2007) 490, p. 2 of 20
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-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.
KEY WORDS
D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), water-soluble
vitamin E, foods for particular nutritional uses, supplement for foods for special
medical purposes, vitamin E deficiency, CAS Registry Number 9002-96-4.
1
In this opinion, the term “TPGS-400” is used for d-α-Tocopheryl polyethylene glycol-400 succinate.
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EFSA Journal (2007) 490, p. 3 of 20
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.
ASSESSMENT
Chemistry
d-α-Tocopheryl polyethylene glycol-1000 succinate (TPGS) is a “water-soluble”
source of vitamin E. It is formed by the esterification of polyethylene glycol 1000
with d-α-tocopheryl succinate. Chemically it is a mixture composed principally of the
monoesterified polyethylene glycol 1000 (70-87 %), the diesterified polyethylene
glycol 1000 (<12 %), free polyethylene glycol 1000 (<12 %), and free tocopherol
(<1.5 %).
A typical sample contains 27 % d-alpha-tocopherol, 65 % polyethylene glycol 1000
and 8 % succinic acid and has a total alpha-tocopherol potency of 260 mg/g TPGS
(387 IU/g), after saponification of the esters. The chemical name is 2R,4’,8’R, αtocopheryl polyethylene glycol 1000 succinate; and the CAS registry number is 900296-4. Since the molecular weight of polyethylene glycol is 1000, the molecular
weight of TPGS is calculated to be approximately 1513 Daltons. The molecular
formula is C33 O5 H54 (CH2 CH2 O)n, where "n" represents the number of polyethylene
oxide moieties attached to the acid group of d-alpha tocopheryl succinate.
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TPGS can be identified by Fourier transform infrared spectrometry (FT-IR).
Properties and proposed specifications
Appearance: Waxy solid, white to light brown; Identity: Measured by FT-IR
spectroscopy; Potency: 260-300 mg d-α tocopherol/g (after saponification of the
ester); Acid value: Not more than 1.5 %; Colour: Not more than 10 (Gradner scale);
Specific rotation: Not less than +24.
Purity
TPGS is composed principally of the monoesterified polyethylene glycol 1000 (70-87
%), the diesterified polyethylene glycol 1000 (<12 %), free polyethylene glycol 1000
(<12 %), and free tocopherol (<1.5 %).
The composition can be measured by HPLC using a light scattering detector.
Impurities
The petitioner mentions that possible impurities may include:
Oxidised TPGS monoester
Succinic acid ester of TPGS monoester
PEG ester impurity of succinic acid ester of TPGS
Propionate ester of TPGS monoester
Methyl ester of tocopheryl succinate
Ethyl ester of tocopheryl succinate
Diester of succinic acid with TPGS monoester
Alpha-tocopherol succinate
Campesterol ester of tocopheryl succinate
Sitosterol ester of tocopheryl succinate
Other sterol ester of tocopheryl succinate
Heavy metals determined as lead:
Upper limits
0.6%
1.5%
0.25%
1.5%
0.25%
1.5%
0.5%
0.25%
0.5%
0.5%
0.5%
not more than 10 mg/kg
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EFSA Journal (2007) 490, p. 5 of 20
Manufacturing process
No information on the manufacturing process has been made available.
Method of analysis in food
The level of vitamin E can be determined in foods by HPLC.
Information on analysis of TPGS in food was not provided by the applicant.
Reaction and fate in food, stability
Stability tests have been carried out on a food for special medical purposes for a
patient with liver disease. The product was a powdered nutritionally complete food
with whole proteins and added TPGS. The vitamin E content slowly decreased from
120 mg/100 g food to 117 mg/100 g after 9 months and 109 mg/100 g after 24
months. This demonstrates the stability of TPGS in this food matrix.
TPGS is unstable in aqueous solution under extreme acidic and alkaline conditions,
due to hydrolysis of the ester linkages. However, it is unlikely that the manufacture,
processing, or composition of a food for special medical purposes would lead to such
conditions. TPGS can also react with strong oxidising agents.
Case of need and proposed uses
TPGS is added to foods for special medical purposes (FSMP), which are used to
provide nutritional support or supplementary feeding for infants and young children
with acute and chronic liver disease. Children with (chronic liver) disease are at high
risk of malnutrition, especially in cholestatic liver disease when onset is in infancy.
The prevalence of malnutrition among these children is significant (Sokol et al. 1990;
Beath et al. 1993; Holt et al., 1997). Vitamin E absorption is adversely affected by
bile salt deficiency and pancreatic insufficiency. Vitamin E malabsorption and
deficiency occur in up to 60-70 % of children with prolonged forms of neonatal
cholestatis leading to a degenerative neurological disorder if the deficiency persists
past 18-24 months (Argao et al., 1993). Correction of the deficiency before the age of
3 years reverses or prevents the development of neuromuscular symptoms.
TPGS does not require the action of bile salts or pancreatic enzymes for absorption
into the intestinal wall (Traber et al., 1986; Traber et al., 1988). TPGS is intended to
be used as a source of vitamin E in FSMP in conditions where insufficient amounts of
bile are secreted, such as in cholestatic liver disease, or where insufficient amounts of
pancreatic enzymes are secreted, such as in cystic fibrosis (Sokol et al., 1987a,b,
Sokol et al., 1993). However, as the presence of secreted bile salts appear to inhibit
the absorption of water miscible forms of vitamin E, such as TPGS (Dimitrov et al.,
1996), it is not advisable to use TPGS in individuals with preserved lipid absorption
and normal vitamin E homeostasis (Sokol et al., 1987a,b). The FSMPs in which
TPGS is to be used will be powdered, liquid, or solid forms as appropriate. TPGS has
practically no taste and lacks bitterness; this makes it especially suitable for oral use.
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TPGS is currently used as a 20% aqueous solution (20% of TPGS by weight or 77.4
IU vitamin E/ml of solution) (Sokol et al., 1993; Socha et al., 1997; Collnot et al.,
2006).
According to the petitioner, the estimated maximum level of TPGS added to a
nutritionally complete food for special medical purposes is approximately 58 mg/100
g product. This has been calculated, based on the maximum level of 0.75 mg vitamin
E/100 KJ food permitted according to Directive 1999/21/EC on dietary foods for
special medical purposes and the energy content of pre-existing nutritionally complete
foods used for patients with liver diseases.
TPGS contains 27 % d-α-tocopherol and each gram of TPGS contains 387 IU (260
mg) d-α-tocopherol.
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.
Age
Estimated
energy
requirement
KJ/day(*)
1 month
6 month
12 month
24 month
36 month
6-7 years
10-11 years
14-15 years
17-18 years
1900
3200
4000
5000
6000
7700
8730
10890
12000
Average
body weight
(kg)(*)
4
8
10
12.5
15
22
33
53
64.5
Estimated
dietary exposure
(mg vit. E/day)
Estimated dietary
exposure to TPGS
(mg/day)
Estimated dietary
exposure to TPGS
(mg /kg bw /day)
14.25
24
30
37.5
45
57.75
65.5
81.7
90
54.9
92.4
115.5
144.4
173.3
222.4
252.2
314.6
346.5
13
11
11
11.5
11.5
10.1
7.6
5.9
5.4
(*) as reported in SCF (1993) for males
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Biological and toxicological data
Bioavailability of d-α-tocopherol from TPGS
In vitro studies
When human fibroblasts, erythrocytes and human intestinal cells (from a cell line)
were incubated with TPGS, the total cellular tocopherol content increased (Traber et
al., 1988; Carini et al., 1990). The results suggest that addition of the hydrophobic
molecule tocopherol to polyethylene glycol 1000 leads to the formation of micelles
that readily pass through cell membranes, and that TPGS enters the cells unchanged
where it is then hydrolysed enzymatically to release free tocopherol (Traber et al.,
1988).
The use of TPGS as an oral absorption enhancer has been discussed by Collnot et al.
who studied the influences of the PEG chain length in TPGS on apical efflux
transporters in Caco-2 cell monolayers by measuring rhodamine 123 transport at
different chain length. An inverse relationship between chain length and the
efficiency of the transport was observed (Collnot et al., 2006). However, it remains to
be established whether such an effect also occurs in vivo.
Animal studies
Traber et al. (1986) performed an absorption study of vitamin E in water miscible
forms
in thoracic duct-cannulated cats. It was concluded that TPGS delivers α-tocopherol to
enterocytes in the absence of bile salts. As α- or γ-tocopherols normally require the
presence of bile salts to be absorbed the authors proposed a hypothesis for the
mechanism of enhanced α-tocopherol absorption from TPGS on the basis of TPGS
micelles formation.
Human studies
Traber et al. (1986) performed a trial with an 8-year-old patient who had suffered
neurological hallmarks of vitamin E deficiency, including loss of muscle
coordination. The trial was performed using either tocopheryl acetate emulsified with
medium-chain tri-glycerides and polysorbate 80 (known as MCT-E) or TPGS. The
results showed higher concentrations of tocopherol in plasma, erythrocytes, and
adipose tissues, and thus better bioavailability after administration of TPGS than after
administration of MCT-E.
Sokol et al. (1987a) studied the bioavailability of d-α-tocopherol from TPGS in 22
children (7 months to 19 years) with severe cholestasis and vitamin E deficiency who
were unresponsive to massive oral doses (100 to 200 IU/kg/day) of dl-α -tocopherol.
The results showed that the bioavailability of d-α-tocopherol from TPGS was superior
to that from d-α-tocopherol alone in these children. An oral dose of 15-25 IU vitamin
E/kg body weight per day from TPGS corrected the vitamin E deficiency state over 1
- 19 months (mean 10.6 months).
Sokol et al. (1985) had previously shown that long-term correction of vitamin E
deficiency by intramuscular administration of dl-α-tocopherol improved the
neurological function in 14 children with chronic cholestasis. Therefore, Sokol et al.
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EFSA Journal (2007) 490, p. 8 of 20
(1987b) also studied the effect of oral TPGS administration on the neurological
function in 12 children with prolonged neonatal cholestasis and with vitamin E
deficiency (aged 9 months to 6 years). Administration of 15 - 25 IU/kg bw/day from
TPGS for a mean of 19.3 months normalised the biochemical serum indices of
vitamin E status and was well tolerated by all patients. The neurological functions as
assessed by serial neurological examinations remained normal in the two children
younger than 3 years at the onset of the study without neurological symptoms,
improved in six of seven children with neurological symptoms and younger than 3
years at onset of the study, and improved in all three children older than 3 years with
neurological symptoms at study start.
Traber et al. (1994) performed a 3 year supplementation study with orally
administered TPGS in a male 71-year old patient suffering from Crohn’s disease. The
supplementation was adjusted twice during the three-year period. Initially, liquid
TPGS was administered with meals. The patient consumed variable amounts of the
preparation, namely 4000 IU/day (10.3 g TPGS/day; 387 IU vitamin E/g TPGS ) at
least four times per week (as stated by the patient) and no less than 1250 IU/day (3.2
g TPGS/day) for the remainder of the week. After 100 weeks of supplementation, a
commercially available preparation of encapsulated solid TPGS was tested in order to
make the vitamin E supplementation more convenient for the patient. Capsules were
given for 4 months at an average of 2500 IU/ day (6.4 g TPGS/day). As the plasma αtocopherol remained unacceptably low, supplementation with liquid TPGS was
reinstated at a dose of 4000 IU/day until the test period was finished at week 173.
After this treatment the patient had normal plasma alpha-tocopherol concentrations.
Administration of deuterium-labelled TPGS to this patient demonstrated that TPGS
was absorbed and the released alpha-tocopherol was transported in lipoproteins. The
disappearance curves of the deuterated alpha-tocopherol in plasma, red cells and
lipoproteins were parallel to those seen in control subjects, suggesting normal
metabolic turnover of the absorbed α-tocopherol.
A trial with TPGS was performed to determine the long-term efficacy in increasing
the vitamin E bioavailability (duration varying from 2 months to 7 years) and safety
of TPGS in children with chronic cholestasis. Sixty vitamin E deficient children (aged
0.5-20 years) with chronic cholestasis and unresponsive to 70-212 IU/kg bw/day of
oral vitamin E entered a trial with TPGS. After an initial evaluation, the treatment was
started with 25 IU Vitamin E/kg body weight per day from TPGS. Vitamin E status
and neurological function quantified by a specific scoring system were monitored
during the study. All children responded to TPGS with normalisation of vitamin E
status. The neurological function, which had deteriorated before entry into the trial,
improved in 25, stabilized in 27, and worsened in only 2 children after a mean of 2.3
years of treatment. It was concluded by the authors that orally supplemented TPGS at
a level of 20-25 IU vitamin E/kg bw/day appears to be an effective form of vitamin E
for reversing or preventing vitamin E deficiency during chronic childhood cholestasis
(Sokol et al., 1993).
Socha et al. (1997) studied the effects of long-term TPGS supplementation (1 year) in
15 children aged from 9 months to 3.4 years (median 1.3 years), having chronic
cholestasis with low serum vitamin E concentrations (median 1.95 mg/L with range
0.8 - 3.7 mg/L). The previous supplementation of alpha-tocopherol was replaced by a
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20 % solution of TPGS, given as one daily dose of 20 IU vitamin E/kg body weight.
Serum α-tocopherol was measured at baseline and again after 1 month in all 15
children and after 1 year in 11 children. Median α-tocopherol levels were
significantly increased after 1 month (median 6.9 mg/L with range 4.4-8.4 mg/L) and
rose further after 1 year (median 9.7 mg/L with range 7.2-14.9 mg/L); similar results
were obtained for the ratio vitamin E/total lipids. It was concluded by the authors that
oral TPGS supplementation of cholestatic children can quickly normalise serum
vitamin E levels.
In a study in healthy human subjects, plasma α-tocopherol concentrations were
determined after supplementation with water- or fat-soluble vitamin E. Administration
of various amounts of TPGS (400 IU [269 mg], 800 IU [537 mg] and 1200 IU [807
mg] ) were applied either as single doses or as repeated doses during 4 weeks. TPGS
given as a single dose resulted in a slight elevation of the plasma α-tocopherol
concentration. The repeated administration of TPGS revealed also a slight elevation
of the α-tocopherol plasma concentration, whereas the administration of fat-soluble
vitamin E led to a significant increase of the plasma α-tocopherol concentration
(Dimitrov et al., 1996). These studies show that the bioavailability of Vitamin E from
TPGS is low in normal healthy humans.
Absorption, metabolism, distribution, and excretion
Animal studies
The absorption, distribution and excretion of polyethylene glycol 1000 (PEG 1000)
from TPGS in rats were evaluated in two studies conducted by Beilman et al.
(1988a,b). A third study conducted concurrently evaluated the absorption, disposition
and excretion of pure PEG 1000 (Beilman et al., 1988c). In the first study (Beilman et
al., l988a) six male rats were gavaged with 360 mg TPGS/kg bw, containing 10 μCi
of [14C]-labelled PEG 1000. Urine, faeces, and cage washings were collected at 12, 36
and 60-hours post-exposure. The animals were killed after 60 hours and tissues and
carcasses were collected for analysis of residual radioactivity. A total of 91 % of the
radioactivity administered was recovered. The largest amount (77%) was recovered in
the faeces, with 31 % collected in the first 12 hours and 40% in the 12— 36 hours
period. A total of 13 % was found in urine with almost 90% of this fraction (11.5 %)
collected during the first 12 hours; cage washings accounted for a total of 0.8%. On
average, 0.6% was identified in the body with most of this being present in the
stomach (0.1 %) and large intestine (0.1 %),
In the second study, animals were divided into 7 groups of 3 animals each and
administered a single gavage dose of 60 mg TPGS/kg bw containing 10 μCi of [14C]labelled PEG 1000. Animals were then killed at 0, 1, 3, 6, 12, 24, and 48 hours post
dosing. In addition to faeces and urine, the following tissues were analysed for
radioactivity at each time point: blood, stomach, small intestine, large intestine, heart,
lung, liver, spleen, kidney and brain. Almost all the radioactivity was eliminated from
the stomach within 1 hour and with 1% remaining after 6 hours. The radioactivity
largely disappeared from the small intestines between 3-6 hours with 2 % remaining
at 24 hours and 0.6 % after 48 hours. Fecal elimination was not complete until after
24 hours by which time cumulative totals exceeded 72 % of the dose. Apparent transit
times in the stomach, small intestine and large intestine were 1, 11 and 21 hours,
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respectively only traces of radioactivity could be found in other tissues examined,
with the liver accounting for the highest levels measured after 6 hours. Most of the
radiolabel was again located in the faeces with 85.3 % recovered after 24 hours.
These results are similar to those obtained in the previous study, demonstrating rapid
and predominantly faecal elimination of the radiolabelled material from the body
(Beilman et al., 1988 b).
In the third study by Beilman et al. (1988c) six male rats were orally gavaged with
240 mg PEG 1000/kg bw corresponding to 10 μCi of [14C]-labelled PEG 1000 by
gavage. Urine and faeces were collected at 12, 36 and 60 hours post-exposure, while
cage washings were collected at 12 and 36 hours. The animals were killed after 60
hours and tissues and carcasses were collected for analysis of residual radioactivity.
The largest amount of radioactivity, 95.3 %, was recovered in the faeces with 68.4 %
collected in the first 12 hours and 26.1 % in the 12 —36 hour period. Less than 1 %
was recovered after 36 hours. A total of 6.7 % was excreted in urine with 6.2%
collected during the first 12 hours. Cage washings accounted for a total of 0.3 % of
radioactivity. No residual radioactivity was found in any of the examined tissues.
These results demonstrated that an oral exposure to PEG 1000 is rapidly eliminated,
with faeces being the primary route of excretion and that a minimum of 6.7 % of PEG
may be absorbed under these conditions (reflected in the excretion in urine after 36
hours).
Human studies
In the study by Sokol et al. (1987a) in 22 children (7 months to 19 years) with severe
cholestasis and vitamin E deficiency given chronic oral doses of 15-25 IU vitamin
E/kg body weight per day from TPGS it was also shown that absorption of PEG 1000
from TPGS in teenage children with chronic cholestasis was similar to that in normal
adults. Thus, 1.7% ± 1.6% of the administered PEG 1000 contained in the TPGS was
excreted in the urine of the 13 persons analysed by HPLC method, compared with 3.0
% ± 1.3 % in 4 normal adults.
Although only a small amount (less than 5 %) of PEG 1000 contained in the TPGS
appeared to be absorbed and readily excreted in the urine, Sokol et al. (1987 a,b)
considered that at high dose levels of TPGS there is a possibility of the induction of a
hyperosmolar state if TPGS is administered during renal insufficiency or dehydration,
since excretion of the PEG 1000 relies completely on glomerular filtration and urinary
excretion. Therefore, the authors recommended that TPGS should not be administered
in children with significant renal insufficiency.
Interaction with other dietary components
TPGS can form micelles and pass through cell membranes (Argao et al., 1992). As no
binding proteins or carriers are required for its uptake into the intestinal cells, it is
unlikely that it has to compete with other nutrients and there is no evidence to suggest
that TPGS will adversely affect the absorption of other nutrients. There is, however,
evidence that TPGS can enhance the absorption of fat-soluble molecules (Argao et
al., 1993).
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Toxicological data
Acute toxicity
The acute oral toxicity of TPGS was evaluated in mature and neonatal (2 day old) rats
(Krasavage and Terhaar, 1977). No mortalities were induced by TPGS in adult
animals (l0/sex) exposed to a single oral dose of 7,000 mg/kg bw in corn oil. In male
neonatal rats mortality rates of 6/17 (35 %), 7/15 (47%) and 10/15 (67 %) were seen
after single doses of 1899, 2981 and 4478 mg TPGS/kg bw, respectively. However,
no LD50 was calculated due to many deaths caused by gavage errors. In other oral
exposure studies no mortalities, gross necropsy findings or clinical signs were noted
in rats following single exposure to 4000 or 5000 mg TPGS/kg bw or higher (Ludwig
and Ames, 1959; Shepard, 1989). In Beagle dogs (2 males), the only abnormal
clinical sign following oral gavage of TPGS (2,000 mg/kg bw) was loose stools the
morning on the day after its administration (SRICC, 1999a).
Subchronic toxicity
Groups of rats (6/sex/dose) were fed diets containing TPGS at levels of approximately
0, 1, 2, 4, 8, and 16% (equivalent to 0, 500, 1000, 2000 and 4000 mg TPGS/kg
bw/day). After 10 weeks the animals fed the 8 and 16% TPGS diets were sacrificed
and their tissues examined microscopically while the remainder animals continued on
their diets for a total of 60 weeks. After 10 weeks no differences were observed in
food consumption and weight gains between the controls and treated groups. No
significant findings associated with TPGS exposure were noted during gross (all
animals) and microscopic analyses (2/sex) of the 2 treated groups. Following 60
weeks of exposure, mortalities were 7/12, 5/12, 2/12 and 7/12 in the 0, 500, 1000 and
2000 mg TPGS/kg bw/day groups, respectively. All animals were noted to be
suffering from respiratory infections. No significant findings attributable to TPGS
exposure were noted between controls or any of the three treated groups during gross
and microscopic analyses (Ludwig and Ames; 1959).
A 91-day toxicity study was conducted in rats (30/sex/dose) with TPGS present in the
diet at levels of 0.002, 0.2 and 2.0 % ( equivalent to 1.0 100 and 1000 mg TPGS/kg
bw/day for males and 1.14, 116 and 1108 TPGS/kg bw/day for females ) (Krasavage
and Terhaar, 1977). The study included analyses of clinical signs, body weights, food
consumption, haematology (an additional haematological examination was done at
day 42 on high-dose and control animals), serum biochemistry, urinalysis, organ
weights and macro- and microscopic evaluations on a comprehensive list of tissues
selected for complete necropsies. No consistent treatment related effects were
observed in the study. It was concluded that the NOAEL was 2% TPGS in the diet.
This is approximately equivalent to 1000 mg TPGS kg bw/day for males and females,
respectively, the highest doses tested.
A one-year oral gavage study in rats (25/sex/dose level) was conducted with TPGS
administered in deionised water at 0, 100, 300 and 1,000 mg/kg bw/day (NCI, 1994a).
The study included clinical observations, measurement of body weights and food
consumption, ophthalmoscopical signs, haematology, serum biochemistry, urinalysis,
11
TPGS in food for special medical purposes
EFSA Journal (2007) 490, p. 12 of 20
determination of organ weights and macro- and microscopic evaluations on a
comprehensive number of tissues. All animals survived to the end of the study and no
treatment-related findings were noted at any exposure level. The NOAEL was
concluded to be 1,000 mg/kg bw/day, the highest dose tested. A similar one-year
study was conducted in dogs (4/sex/dose) using essentially identical methodology and
dose levels (NCI, 1994b). In this study two intercurrent deaths were seen, which were
not related to the TPGS treatment. No treatment related effects were noted in any
parameter examined and the NOAEL was concluded to be 1,000 mg/kg bw/day, the
highest dose tested.
Reproductive and developmental toxicity
A one-generation, two litter reproduction and teratology study (Krasavage and
Terhaar, 1977 was conducted in rats (15/sex/dose) exposed to TPGS in their diets at
levels of 0.002, 0.2, and 2.0 % (equivalent to approximately 1.0, 100 and 1000 mg
TPGS/kg bw/day). The females, designated F0, were mated with treated males after
112 days of TPGS exposure to produce the F1a litters. The F0 -females were mated
again (using different males) after 175 days of exposure to produce F1b offspring. The
F1 animals were maintained on test diets for 5 weeks post-weaning and 4 animals
(2/sex) from each litter were randomly chosen for microscopic analysis of their
tissues. Haematological analysis was performed on the high dose and control F0
animals 2 weeks prior to study termination and complete histological examinations
were performed. These animals had been maintained on the test diets for a total of
265-268 days. The reproductive parameters examined were insemination index,
fertility index, gestation index, viability index and lactation index. In addition, the
mean gestation period, litter size, sex ratio, pup and parent mortalities, and the mean
body weights of the pups per litter at four days of age, at weaning and at one and two
weeks after weaning were recorded. The results showed that the exposure to TPGS
did not induce alterations in any of the reproductive parameters studied and similarly,
no indications of toxicity were noted. The NOAEL was concluded to be 2% in the
diet, equivalent to approximately 1500 mg TPGS/kg bw/day, the highest dose level
tested.
Groups of 15 pregnant rats received diets containing 0, 0.002, 0.2, and 2.0% of TPGS
(equivalent to approximately 0, 1.0, 100, 1000 mg TPGS/kg bw/day). The test diets
were given on days 6 to 17 of gestation and the animals were killed on day 20. The
parameters studied included total implantation sites, resorptions, and total number,
weight and sex of live fetuses. All fetuses were examined for external abnormalities
and half of them were fixed and dissected for soft tissue evaluations. Gross anomalies
seen in only two fetuses from the TPGS-treated groups were considered by the
authors to be spontaneous and not attributable to the ingestion of TPGS. Thus, the
maternal and developmental NOAEL for dietary TPGS was 2.0% TPGS in the diet,
equivalent to approximately 1000 mg TPGS/kg bw/day, the highest dose level tested
(Krasavage and Terhaar, 1977).
In a second rat study, the effect of TPGS on embryo-fetal, pre- and post-natal
development, and maternal function was assessed. TPGS was administered from the
time of implantation to weaning by oral gavage at doses of 100, 300 or 1,000 mg/kg
bw/day. The parameters evaluated in the dams included clinical observations, body
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EFSA Journal (2007) 490, p. 13 of 20
weight changes and food consumption. The fetuses and offspring were assessed for
external and visceral and skeletal changes, viability, clinical observations, body
weight changes, postnatal development, reflex responses in open field performance,
learning ability, and reproductive ability of the offspring. No effects due to TPGS
exposure were noted in any endpoints in either the dams or their offspring at 1000
mg/kg bw/day. Thus the NOAEL was 1000 mg TPGS/kg bw/day, the highest dose
level tested (SRICC, 1999d).
Developmental toxicity of TPGS was also assessed in rabbits (SRICC, 1999b,c). The
test material was administered by oral gavage at doses of 100, 300 or 1000 mg/kg
bw/day on days 6 -18 of gestation in a preliminary study and in the main study. In the
preliminary study soft faeces, decreased food consumption and a concomitant
decrease in body weight gain was observed in the dams at the highest dose. These
effects were not observed in the main study. No treatment related effects were
observed at any dose in external, visceral or skeletal examinations of the fetuses. The
NOAEL for fetal effects was 1000 mg/kg bw/day, the highest dose level tested.
Chronic toxicity and carcinogenicity
No chronic toxicity and carcinogenicity studies are available on TPGS. However,
recent limited carcinogenicity studies (only one dose group) in mice and rats are
available on a structurally closely related compound, “TPGS-4002” containing PEG
400 instead of PEG 1000.
Crl:CD-1 (ICR) BR VAT plus mice and Han Wistar (Glx:HAN, WlfBR) rats (30
animals/sex/group) were dosed with aqueous solutions of “TPGS-400” at dose levels
of 1131 and 1414 mg/kg bw/day by oral gavage 7 days a week, respectively. Similar
groups of animals received deionised water as controls. The duration of the
experiments were 104 weeks. Survival, clinical signs of toxicity, and body weights
were recorded during the course of the study. Haematology and macroscopical and
microscopical examinations of tissues were performed on all animals. “TPGS-400”
had no effects on these parameters and did not increase the tumour incidences in
either species (Serota and Slone, 2003a, 2003b).
Genotoxicity
TPGS was tested for reverse mutations in Salmonella typhimurium strains TA98, TA
100, TA 1535 and TA 1537 and Escherichia coli WP2uvrA with or without metabolic
activation by the pre-incubation method. Two independent studies were conducted
using up to 5,000 μg/plate. No increases in revertant colonies were seen (SRICC,
1998a).
TPGS did not induce chromosomal aberrations in Chinese hamster lung cells at
concentrations of 25 to 200 μg/ml, 10 to 80 μg/ml, or 7.5 to 60 μg/ml TPGS for 6, 24
and 48 hours, respectively, without metabolic activation. Similar results were seen
following a 6-hour incubation in concentrations up to 1,600 μg/ml with metabolic
activation (SRICC, 1998b).
2
In this opinion, the term “TPGS-400” is used for d-α-Tocopheryl polyethylene glycol-400.
13
TPGS in food for special medical purposes
EFSA Journal (2007) 490, p. 14 of 20
In an in vivo micronucleus assay, rats were administered TPGS by oral gavage at
single doses up to 2,000 mg/kg body weight. Bone marrow preparations were made
24 hours after dosing. There was no difference in the frequency of micronuclei or in
the ratio of polychromatic erythrocytes to normochromatic erythrocytes between the
treated groups and the negative control group (SRICC, 1998c).
Human data
In the study by Sokol et al. (1987a) in 22 children (7 months to 19 years) with severe
cholestasis and vitamin E deficiency, oral doses of 15-25 IU vitamin E/kg body
weight per day, equivalent to 38.8 –64.6 mg TPGS/kg bw per day, did not produce
clinical or biochemical evidence of gastrointestinal, renal, hepatic, or haematological
toxicity
In the study by Sokol et al. (1993) where 60 vitamin E deficient children (aged 0.5-20
years) with chronic cholestasis were given 25 IU vitamin E/kg body weight per day
from TPGS (duration varying from 2 months to 7 years) clinical and biochemical
parameters (serum bilirubin, aspartate amino-transferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (AP) and cholesterol concentrations) were
monitored throughout the study. No adverse effects related to the TPGS
administration were observed as judged by these parameters and the authors
concluded that oral administration of TPGS at a level of 20-25 IU/kg bw/day,
equivalent to 64.6 mg TPGS/kg body weight per day appears to be safe in children
suffering chronic cholestasis (Sokol et al., 1993).
Socha et al. (1997) studied the effects of TPGS supplementation for one year on lipid
peroxidation and polyunsaturated fatty acid status in serum from 15 children aged
from 9 months to 3.4 years (median 1.3 years). TPGS was given as a daily dose of 20
IU vitamin E/kg body weight, equivalent to 51.7 mg TPGS/kg body weight per day.
Plasma lipid peroxidation expressed as thiobarbituric acid-reactive substances
concentration (TBARS) and plasma phospholipid fatty acid profile were estimated at
baseline and after 1 month in all 15 children, and after one year in 11 children.
TBARS concentrations were significantly higher in cholestatic children at baseline
than in the control group, but did not change significantly during the TPGS
administration. Compared with the controls, the contributions from polyunsaturated
fatty acids to total phospholipid fatty acids were markedly decreased in cholestatic
patients at baseline, but did not show major changes after one year of TPGS
supplementation. Bilirubin, alanine amino-transferase (ALAT), alkaline phosphatase
(AP) and gamma-glutamyl transferase (gamma-GT) were higher in the cholestatic
children than the reference values but did not further increase during the one year
treatment with TPGS. It was concluded by the authors that oral TPGS
supplementation did not alter the increased lipid peroxidation and poor
polyunsaturated fatty acid status in cholestatic children.
DISCUSSION
D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a “water soluble”
vitamin E source, in contrast to other vitamin E sources, which are lipophilic. TPGS is
intended to be used in patients (mainly infants and children) with impaired vitamin E
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TPGS in food for special medical purposes
EFSA Journal (2007) 490, p. 15 of 20
absorption due to fat malabsorption. The bioavailability of vitamin E and its other
lipid-soluble sources depends on fat absorption and therefore 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. TPGS can form micelles and thus is able to pass the waterlayer in the intestine and reach the enterocytes, readily enabling the absorption of the
intact TPGS molecule. In vitro studies have shown that TPGS can be hydrolysed in
enterocytes to release α-tocopherol and bioavailability studies in patients with
cholestatic liver disease have shown that TPGS administration can correct impaired
vitamin E bioavailability. However, studies in normal healthy humans showed that
administration of TPGS, in contrast to fat-soluble vitamin E sources, only slightly
elevated plasma α-tocopherol. Therefore, TPGS is not a useful source of vitamin E in
normal, healthy humans.
Several ADME studies in rats using TPGS radiolabeled in the polyethylene glycol
1000 (PEG 1000) moiety showed that radioactivity was to some extent absorbed and
distributed throughout the body. The administered radioactivity was readily
eliminated, mainly in faeces (about 72-85% in 24 hours) and urine (7-13% in 24
hours). After 60 hour no residual radiolabel was found in any tissues. In teenage
children with chronic cholestasis 1.7% of the administered PEG 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
main species used for the safety studies on TPGS).
This pattern of absorption and excretion of PEG 1000 is consistent with many studies
in animals and humans on other PEGs previously evaluated by the Panel (EFSA
2006). Generally, these studies demonstrate that the extent of PEG absorption
depends on the molecular weight of the specific polymer, such that more complete
absorption has been reported for lower molecular weight PEGs, like PEG 400, while
absorption is much more limited in case of heavier PEGs. Once absorbed PEGs are
excreted in the urine by glomerular filtration without tubular reabsorption (EFSA
2006).
According to some investigators, at high dose levels of TPGS there is a possibility of
the induction of a hyperosmolar state if TPGS is administered during renal
insufficiency or dehydration, since excretion of the PEG 1000 relies on glomerular
filtration and urinary excretion. Therefore, the authors recommended that TPGS
should not be administered to children with significant renal insufficiency.
As TPGS does not have to compete for transport carriers no interaction with other
nutrients are known. If tocopheryl acid succinate were formed by hydrolysis, the
absorption by individuals with fat malabsorption would be negligible.
The studies combining bioavailability, tolerance and the impact of TPGS on
neurological effects caused by vitamin E deficiency in patients revealed that no
adverse effects of TPGS supplementation were observed at dose levels up to 64.6
mg/kg bw/day
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TPGS in food for special medical purposes
EFSA Journal (2007) 490, p. 16 of 20
The toxicological data reveal that TPGS is of low acute toxicity. Furthermore a
number of subchronic toxicity studies, a one-generation reproduction study, and a few
developmental studies in rats and one study in rabbits revealed no adverse effects at
dose levels equivalent to 1000 mg TPGS/kg body weight per day or higher.
Genotoxicity studies of TPGS consisting of one in vitro bacterial (Salmonella and
Escherichia coli) test, one in vitro chromosomal aberration test in Chinese hamster
lung cells and one bone marrow micronucleus test in rats revealed that TPGS did not
have genotoxic properties. The toxicity file also included two limited chronic toxicity
and carcinogenicity studies in rats and mice using “TPGS-400” containing PEG-400
instead of PEG-1000 and therefore would be expected to provide a higher systemic
exposure to PEG. However, no toxic effects including carcinogenicity was observed
in rats and mice after doses of 1131 mg/kg bw/day (mice) and 1414 mg/kg bw per day
(rats) for 2 years, respectively. 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 subchronic
toxicity studies. TPGS is only to be used for food for special medical purposes under
medical supervision at estimated exposure varying from 5 mg TPGS /kg bw in
teenagers to 13 mg TPGS /kg bw in 1 month old infants. Potential exposure would be
lower in adults. This provides an adequate margin of exposure of 80 to 200. The Panel
considered also that in some human studies dose levels up to 64.6 mg/kg bw/day did
not reveal any adverse effect in the parameters studied (liver, kidney).
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 group ADIs established by the SCF (5 mg/kg bw for PEG 300 - 4000) and
JECFA (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.
CONCLUSION
The Panel therefore concluded that the use of TPGS in foods for special medical
purposes is not of safety concern at the anticipated intake level. However, the Panel
noted that it is advised not to apply the TPGS treatment in children with severe
impairment of kidney function.
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.
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EFSA Journal (2007) 490, p. 17 of 20
DOCUMENTATION PROVIDED TO EFSA
Submission to SCF for the safety evaluation of D-alpha-tocopheryl polyethylene
glycol 1000 succinate and additional detailed data further sent to EFSA on request.
Dossier submitted by SHS International Ltd on behalf of IDACE.
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SCIENTIFIC PANEL MEMBERS
Fernando Aguilar, Herman Autrup, Sue Barlow, Laurence Castle, Riccardo Crebelli,
Wolfgang Dekant, Karl-Heinz Engel, Natalie Gontard, David Gott, Sandro Grilli,
Rainer Gürtler, John Chr. Larsen, Catherine Leclercq, Jean-Charles Leblanc, F.
Xavier Malcata, Wim Mennes, Maria Rosaria Milana, Iona Pratt, Ivonne Rietjens,
Paul Tobback, Fidel Toldrá.
20