INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SAFETY EVALUATION OF CERTAIN
FOOD ADDITIVES
WHO FOOD ADDITIVES SERIES: 42
Prepared by the Fifty-first meeting of the Joint FAO/WHO
Expert Committee on Food Additives (JECFA)
World Health Organization, Geneva, 1999
IPCS - International Programme on Chemical Safety
POLYGLYCITOL SYRUP
First draft prepared by
E.J. Vavasour
Chemical Hazard Assessment Division, Bureau of Chemical Safety, Food
Directorate, Health Protection Branch, Health Canada, Ottawa, Ontario,
Canada
Explanation
Biological data
Biochemical aspects
Biotransformation
Toxicological studies
Short-term studies of toxicity
Observations in humans
Comments
Evaluation
References
1. EXPLANATION
Polyglycitol syrup has not previously been evaluated by the
Committee. Since its components are the same as those of maltitol
syrup, differing only in the relative proportions of sorbitol,
maltitol, and higher-order polyols, the evaluation conducted for
maltitol syrup at the forty-ninth meeting (Annex 1, reference 131) to
accommodate a wide range of starch hydrogenation products, would also
apply to polyglycitol syrup.
At the forty-ninth meeting, toxicological data in support of new
specifications for maltitol syrup were reviewed. Since sorbitol and
maltitol had previously been allocated ADIs 'not specified', only
higher-order polyols required toxicological assessment. The Committee
concluded at its forty-sixth meeting (Annex 1, reference 122) that
proliferative lesions of the adrenal glands induced by some polyols
(including sorbitol and maltitol) were a species-specific response and
were not relevant to the toxicological evaluation of these substances
for humans. Several short-term studies in which rats and dogs were
given materials with a higher-order polyol content exceeding 80% of
the syrup were reviewed at the forty-ninth meeting, as were data on
their metabolic fate.
At the present meeting, the Committee reviewed new data relating
to digestibility in vitro, a short-term study of toxicity in rats
given material with a higher-order polyol content of 78%, and a study
on the effects of hydrogenated starch hydrolysates on the glycaemic
response in diabetic and non-diabetic individuals.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Biotransformation
An immobilized enzyme system of a series of carbohydrases
(alpha-amylase, isomaltase, and maltase) was used to assess the
relative digestibility of a group of hydrogenated starch hydrolysates,
which included a 14:8:78 mixture, a 7:60:33 mixture, a 10.5:34:55.5
mixture, and a 4-8:50-55:37-42 mixture. Although the polyol
distributions of the 7:60:33 and 4-8:50-55:37-42 mixtures are similar,
the higher-order polyols in the former tend to have a higher degree of
polymerization than those in the latter. The hydrogenated starch
hydrolysates produced were partially digested with the immobilized
enzyme system, which resulted in a broadening of the peak
corresponding to hydrogenated saccharides with a degree of
polymerization greater than three, a decrease in the height of the
maltotriitol peak, the appearance of glucose, and an increase in the
height of the maltitol and sorbitol peaks for all of the hydrolysates.
Markedly less sorbitol was produced from the hydrolysates that
contained the highest percentage of highly polymerized saccharides,
the 14:8:78 and 10.5:34:55.5 mixtures; the largest amount of glucose
was produced by the hydrolysate with the highest percentage of highly
polymerized saccharides, the 14:8:78 mixture. The overall
digestibility of hydrogenated starch hydrolysates in this system, as
measured by increased appearance of maltitol, sorbitol, and glucose,
was highest for the products that contained the largest percent of
highly polymerized saccharides, i.e. the first three mixtures. This
was attributed to a higher affinity for or activity of the digestive
enzymes for glucose-glucose bonds than those for glucose-sorbitol
bonds (Allen & Watkins, 1997).
2.2 Toxicological studies
2.2.1 Short-term studies of toxicity
A polyglycitol syrup, the 14:8:78 mixture, two maltitol syrups,
7:60:33 and 7:52:41, and a metabolic control (sorbitol:glucose, 44:56)
were fed to groups of 10 male and 10 female Crl.CD
(Sprague-Dawley-derived) rats for 13 weeks. Two groups were fed
untreated diet, and single groups were fed diets containing 6.7, 13.3,
or 20% 14:8:78 mixture, 20% 7:60:33 or 7:52:41 mixture, or the
metabolic control. The animals were checked twice daily for deaths and
clinical signs and underwent a physical examination weekly. Body
weights and food consumption were calculated on a weekly basis. An
ophthalmoscopic examination was conducted before and at the end of the
study. Blood samples were collected during the last week of the study
for determination of a standard set of haematological and clinical
chemical parameters. Overnight urine samples were also collected
during the last week of the study for determination of urine volume,
calcium ion concentration, and creatinine concentration. After
sacrifice, all rats underwent gross necropsy, and 44 tissues and
organs, including caecum, kidneys, and adrenal glands, were preserved
for histopathological examination. The weights of the adrenals, brain,
empty caecum, kidney, liver, testes, and thyroid/parathyroid were
determined.
No deaths or clinical observations were noted that could be
attributed to an effect of treatment. The body weights of the treated
animals were similar to those of controls. The food consumption of the
four groups receiving 20% liquid carbohydrate material was slightly
increased in comparison with the control groups, but the difference
was generally not statistically significant. The intakes of each of
the substances in treated diets were as follows for males and females:
4.2/4.9, 8.3/9.9, and 13/15 g/kg bw per day of the 6.7, 13, and 20%
14:8:78 mixture; 13/15 g/kg bw per day of the 20% 7:60:33 mixture;
13/15 g/kg bw per day of the 20% 7:52:41 mixture; and 13/16 g/kg bw
per day of the 20% sorbitol-glucose mixture. No effect of treatment
was evident from haematological and clinical chemical examinations,
including the values for serum calcium ion. Statistically
significantly increased total calcium excretion, urinary calcium
concentration, and urinary calcium:creatinine ratio over the values in
both control groups were noted in both males and females. These
parameters were also increased in a dose-related manner in males
receiving 13% and females receiving 6.7 and 13% of the polyglycitol
syrup. The absolute and relative caecal weights in both male and
female rats in the groups receiving 20% liquid carbohydrate in their
diet were increased relative to those of controls. No other
treatment-related effect on organ weights were noted, nor was any
effect apparent from histopathological examinations, in particular in
the adrenals, kidneys, and caecum. Increased caecal weights have been
observed previously in response to ingestion of polyol sugars by rats
and are due to the accumulation of large amounts of undigested,
unabsorbed material in the caecum. The increased fermentation by gut
flora results in lowered pH, which promotes increased absorption of
calcium from the gastrointestinal tract and subsequent excretion of
the excess. Consequently, the effects observed in this study would not
be considered adverse. The NOEL was 13 g/kg bw per day, the highest
dose tested (Goldenthal, 1997).
2.3 Observations in humans
The glycaemic availability of two hydrogenated starch
hydrolysates, the 14:8:78 and 7:60:33 mixtures, was compared with that
of glucose in non-diabetic persons and patients with
non-insulin-dependent and insulin-dependent diabetes mellitus. Each
group consisted of three men and three women, who ranged in age from
31 to 69 years. The effects of ingestion of 50 g per 1.73 m2 of each
substance were determined for a 5-h period, each person receiving one
of the three oral challenges on successive days in a double-blind
cross-over design. Peripheral venous blood samples were collected at
0, 15, 30, 45, 90, 120, 150, 180, 240, and 300 min after ingestion of
the test material for measurement of glucose, insulin, free fatty
acids, and C-peptide. Alveolar breath samples for determination of H2
were collected at 30-min intervals for 4 and 5 h after the test
'meal'. The glycaemic response to the hydrogenated starch hydrolysate
syrups was lower than that to glucose in both diabetic and
non-diabetic subjects. Ingestion of the 7:60:33 mixture induced a
lower glycaemic response than did the 14:8:78 mixture in all groups,
but was most marked in the patients with non-insulin-dependent
diabetes. Persons without diabetes and those with
non-insulin-dependent diabetes released significantly less insulin in
response to the syrups than to glucose, whereas patients with
insulin-dependent diabetes showed no insulin response to any of the
products. C-Peptide responses were increased in persons without
diabetes and those with non-insulin-dependent diabetes in the order
glucose > 14:8:78 > 7:60:33, reflecting differences in glucose
levels resulting from absorption in the small intestinal. Reductions
in plasma free fatty acid concentrations were also observed in
response to the challenges with glucose, which elicited a greater
response than the syrups. Breath H2 levels were unaffected by glucose
challenge, but were increased by the hydrogenated starch hydrolysates
syrups in the order 7:60:33 > 14:8:78, as a result of fermentation of
unhydrolysed, unabsorbed material by the gut flora. These results were
taken to indicate that the glycaemic response to hydrogenated starch
hydrolysate syrups is lower than that to glucose in both diabetic and
non-diabetic individuals. In addition to the lower content of glucose
in the hydrogenated starch hydrolysate syrups, an inhibitory effect of
sorbitol on glucose uptake was considered to affect the glycaemic
response (Wheeler et al., 1990).
3. COMMENTS
Hydrolysis of a polyglycitol syrup composed of 14% sorbitol, 8%
maltitol, and 78% higher-order polyols resulted in production of more
glucose and less sorbitol than products conforming to the
specifications for maltitol syrup, which is consistent with the
relative proportion of glucose released on hydrolysis of each
material. The greater digestibility of hydrogenated starch
hydrolysates with the highest content of highly polymerized
saccharides was considered to be the consequence of a greater activity
or affinity of digestive enzymes for glucose-glucose than for
glucose-sorbitol bonds. Data on the disposition of maltitol syrup
reviewed at the forty-ninth meeting indicated that the higher-order
polyols would be completely hydrolysed to glucose and maltitol or
sorbitol, with a considerable portion undergoing fermentation by the
gut flora. Bacterial fermentation was demonstrated by the detection of
an increased amount of H2 in the breath of human subjects in a study
reviewed at the present meeting.
Inclusion of up to 20% of a polyglycitol syrup (containing
14:8:78 sorbitol:maltitol:higher-order polyols) and two maltitol
syrups (7:60:33 and 7:52:41) in the diet of rats, equal to 13 g/kg bw
per day, for 13 weeks, was not associated with adverse effects. The
only effects observed -- increased weight of the empty caecum and
increased urinary calcium excretion in the absence of elevated serum
calcium -- were considered to be the consequence of the accumulation
of poorly absorbed material in the caecum and to be of no
toxicological significance.
In studies of diabetic and non-diabetic human subjects, ingestion
of polyglycitol and maltitol syrups resulted in a lower glycaemic
response than with glucose, in the order maltitol syrup
< polyglycitol syrup < glucose. These results reflect the relative
proportion of glucose released by hydrolysis of each material.
4. EVALUATION
On the basis of the data on hydrogenated oligo- and
polysaccharides reviewed at the forty-ninth and the present meetings,
the Committee allocated a group ADI 'not specified' to materials
conforming to the specifications for polyglycitol syrup and maltitol
syrup.
5. REFERENCES
Allen, J.C. & Watkins, R. (1997) In vitro digestibility of Hystar
5875, Hystar 6075 and Lycasin 80/55. Unpublished report to Lonza,
Inc., Fair Lawn, New Jersey, USA. Submitted to WHO by the
International Diabetic Federation, Brussels, Belgium.
Goldenthal, E.I. (1997) 13-Week dietary toxicity study in rats with
Hystar(R) liquid carbohydrates products. Unpublished report from MPI
Research, Mattawan, Michigan, USA, to Lonza, Inc., Fair Lawn, New
Jersey, USA. Submitted to WHO by the International Diabetic
Federation, Brussels, Belgium.
Wheeler, M.L., Fineberg, S.E., Gibson, R. & Fineberg, N. (1990)
Metabolic response to oral challenge of hydrogenated starch
hydrolysate versus glucose in diabetics. Diabetes Care, 13, 733-740.
See Also:
Toxicological Abbreviations