HYDROXYPROPYL STARCH
Explanation
This modified starch was previously evaluated for an ADI for man
by the Joint FAO/WHO Expert Committee on Food Additives in 1969, 1971
and 1973 (see Annex I, Refs. 19, 26 and 29). Toxicological monographs
were published in 1969, 1972 and 1974 (see Annex I, Refs. 20, 27 and
30).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and is reproduced
in its entirety below.
Introduction
Modification is carried out by propylene oxide at levels up to
25% and the resultant starch is usually lightly oxidized, bleached or
acid modified after etherification. Substitution may amount to a
maximum of 40 ether linkages per 100 glucopyranose units if 25%
propylene oxide is used, and 4-6 ether linkages per 100 glucopyranose
units if 5% propylene oxide is used.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
In vitro digestibility by pancreatin was estimated by comparing
the amount of reducing material liberated with that formed from native
wheat starch. No significant difference could be detected between low
(1 in 10) and high (4 in 10) substituted starches compared with
unmodified starch (Kay & Calandra, 1962). In contrast, the
digestibility by pancreatin was found to decrease with increased
substitution degree. At 0.04 degree the digestibility was 80% of that
of unmodified starch (Leegwater & Luten, 1971). Cornstarch treated
with propylene oxide -2-C14 to produce hydroxypropyl starch (degree
of substitution 0.12) was given to a male rat by gavage. 92% of the
radioactivity was excreted in the faeces and 3.6% in the urine over
the next 50 hours. The urinary activity was probably derived from
propyleneglycol in the test material (Leegwater, 1971). Further
investigation revealed hydroxypropyl maltose to be the major faecal
metabolite (Leegwater & Speek, 1972; Leegwater et al., 1972).
TOXICOLOGICAL STUDIES
Special studies on propylene chlorohydrin
Propylene chlorohydrin was identified as the residue formed in
foods fumigated with propylene oxide (Wesley et al., 1965). The
chlorohydrin is formed by the reaction of the epoxide with the
chloride of food. Previously, it had been believed that propylene
glycol, formed by reaction with water in the food, was the residue.
Propylene chlorohydrin is also formed in starches modified by
hydroxypropylation. Both propylene chlorohydrin isomers have been
identified in fumigated foods (Ragelis et al., 1966).
When volatilization was precluded, a combination of high
temperature and prolonged time in cooking did not appreciably alter
the propylene chlorohydrin content of food, but when volatilization
was possible, the chlorohydrin content was reduced 50% by cooking
(Wesley et al., 1965). When propylene chlorohydrin was added to a
standard ground laboratory rat diet, 20 minutes of mixing in an open
mixer at room temperature resulted in a 65% decrease in the propylene
chlorohydrin content (USFDA, 1969).
Acute toxicity
LD50
Animal Route (mg/kg bw) Reference
Rat Oral 218 USFDA, 1969
Dog Oral 150 mg/kg - no deaths USFDA, 1969
200 mg/kg - 1/7 deaths
250, 300 mg/kg - 6/6 deaths
Short-term studies
Rat
Groups of 10 male and 10 female 5-week-old rats were fed, for
25 weeks, diets to which propylene chlorohydrin had been added. The
planned dietary levels were 0, 1000, 2500, 5000 and 10 000 ppm
(0, 0.1%, 0.25%, 0.5% and 1.0%) but analysis of the 10 000 ppm (1%)
diet after mixing in the test compound (open mixer, 20 minutes mixing
time, room temperature) showed an actual concentration of 3568 ppm or
35% of the planned level. The 2-chloro isomer constituted 27% of the
total found. The actual level in this diet, after 7 days exposure to
laboratory conditions, was reduced to 838 ppm (.0838%), with 32% of
the 2-chloro isomer, or less than 10% of the planned concentration.
Weight gain in both sexes on the 5000 ppm (0.5%) and the 10 000 ppm
(1%) levels was depressed. The depression was slight in the males on
the 5000 ppm (0.5%) level and both groups of females and moderate in
the males on the 10 000 ppm (1%) level. Food consumption was slightly
decreased in these groups but food efficiency was normal. The average
liver and kidney weights of the males and the liver weight of the
females on the 10 000 ppm (1%) level were decreased but the organ
weight/body weight ratios were normal. The decreased spleen weights
and spleen/body weight ratios in the males and other minor organ
weight variations appeared to be unrelated to the treatment. No
effects on haematological values, mortality, or gross or microscopic
lesions in the tissues were observed (USFDA, 1969).
Propylene chlorohydrin was administered to groups of 10 male and
10 female 8-week-old rats by stomach tube in doses of 0, 25, 50, 75
and 100 mg/kg/day for 22 weeks. The dose for the high level was
increased from 100 mg/kg to 150 mg/kg in the eleventh week, to
200 mg/kg in the fourteenth week, and to 250 mg/kg in the sixteenth
week. Doses of 200 mg/kg and less did not increase mortality. All the
rats on the high level were dead by the nineteenth week, with all but
one of the deaths occurring between the sixteenth and nineteenth
weeks, after the dose had been increased to 250 mg/kg. On the high
level, weight gain was moderately depressed in the males and slightly
depressed in the females while the dose was 100 or 150 mg/kg. Both
sexes lost weight when the dose was increased to 200 mg/kg. Weight
gain was slightly, but not significantly, decreased in both sexes at
the 75 mg/kg level. Food consumption was slightly decreased in the
males of the high level while the dose was 100 mg/kg and decreased to
a greater extent when the dose was raised. The females on the high
level also showed a slight decrease in food consumption when the dose
was increased. With the rats losing weight when the dose was increased
to 200 mg/kg, the food efficiency values have no meaning. The liver
weight/body weight ratios of both males and females on the 75 mg/kg
dose and the liver weight and liver weight/body weight ratio of the
males on the 25 mg/kg dose were increased, but this increase was not
accompanied by gross or microscopic alterations in the liver. Other
organ weight and organ weight/body weight ratio changes did not appear
to be related to the treatment. No haematological effects or gross or
microscopic effects on the tissues of the treated rats, at a dose of
75 mg/kg or less, were seen. The tissues of the high level rats were
not examined microscopically (USFDA, 1969).
Acute toxicity
LD50
Animal Route (mg/kg bw) Reference
Rat Oral 218 USFDA, 1969
Dog Oral 150 mg/kg - no deaths USFDA, 1969
200 mg/kg - 1/7 deaths
250, 300 mg/kg - 6/6 deaths
Short-term studies
Rat
Groups of 10 male and 10 female rats were fed for 90 days
diets containing 0, 2, 5, 10 and 25% of highly modified starch
(25% propylene oxide) and 25% unmodified starch. No systemic toxicity
was noted. There were no adverse effects regarding mortality,
urinalysis or haematology at any level. There was slight reduction in
growth rate at the highest dietary level with lower food utilization
and without an equivalent increase in food consumption. Mild diarrhoea
occurred at the 25% dietary level. No adverse effects occurred at any
other level. At autopsy there were no significant differences in the
organ weights of liver, kidney, spleen, gonad, heart or brain. Gross
and histological examination of all major tissues revealed no
abnormalities due to the feeding of highly modified starch (Kay &
Calandra, 1961). In another experiment groups of 10 male and 10 female
rats were fed for 90 days on diets containing 0, 5, 15 and 45% of low
modified starch (5% propylene oxide). Haematological findings at
12 weeks were comparable for all groups. Body weights did not differ
significantly from controls but were consistently lower in male rats
only. Feed efficiency was similar in all groups. Caecal enlargement
was seen at the 45% and very slightly at the 15% level. No
histological abnormalities were detected in any major organs which
were due to the test substance. The enlarged caeca showed no evidence
of inflammation or changes in the muscular coat (Feron et al., 1967).
The effect of hydroxypropyl starches (of various degrees of
substitution) on caecal size and content constituents was studied in
male rats (Leegwater et al., 1974). Relative caecal weights, both
filled and empty, as well as the severity of diarrhoea, increased with
increasing concentrations in the diet when compared with pre-
gelatinized potato starch controls. Caecal weight also tended to
correlate with the degree of substitution. The caecum was found to
return to normal size within 4 weeks when the hydroxypropyl starch in
the diet was replaced by unmodified, pre-gelatinized starch.
Long-term studies
None available.
Comments
Short-term feeding studies with rats show that many highly
modified starches are well tolerated.
The metabolic study in rats using radio-labelled material shows
that most of the radio-labelled hydroxypropyl-containing moiety is
excreted in the faeces. No long-term study on this modified starch is
available but collateral evidence from the long-term study in rats
with hydroxypropyl distarch glycerol, a more highly modified starch,
indicates that the hydroxypropyl moiety is causing no adverse effects.
The available evidence for the group of modified starches considered,
indicates that caecal enlargement without associated histopathological
changes is without toxicological significance.
EVALUATION
Estimate of acceptable daily intake for man
Not specified.*
* The statement "ADI not specified" means that, on the basis of the
available data (toxicological, biochemical, and other), the total
daily intake of the substance, arising from its use or uses at
the levels necessary to achieve the desired effect and from its
acceptable background in food, does not, in the opinion of the
Committee, represent a hazard to health. For this reason, and for
the reasons stated in individual evaluations, the establishment
of an acceptable daily intake (ADI) in mg/kg bw is not deemed
necessary.
REFERENCES
Feron, V. J., Til, H. P. & de Groot, A. P. (1967) Sub-chronic
toxicity test with a modified potato starch (propylene oxide) and
an alginate in albino rats. Report No. R2456. Centraal Instituut
voor Voedingsonderzoek, Zeist, Holland
Kay, J. H. & Calandra, J. C. (1961) Ceron N - albino rats, 90-day
subacute oral toxicity and Ceron N - rats, 90-day subacute oral
toxicity. Pathologic findings. Report of Industrial Bio-Test
Laboratories, Inc., Northbrook, Ill., to Hercules Powder Company,
Wilmington, Del. Submitted to Federation of American Societies
for Experimental Biology, Bethesda, Md., by Stein, Hall and
Company, Inc., New York
Kay, J. H. & Calandra, J. C. (1962) Starch digestion studies. Report
of Industrial Bio-Test Laboratories, Inc., Northbrook, Ill., to
Hercules Powder Company, Wilmington, Del. Submitted to Federation
of American Societies for Experimental Biology, Bethesda, Md., by
Stein, Hall and Company, Inc., New York
Leegwater, D. C. (1971) Unpublished report No. 3441 by Centraal
Instituut voor Voedingsonderzoek, submitted to WHO
Leegwater, D. C. & Luten, J. B. (1971) A study on the in vitro
digestibility of hydroxypropyl starches by pancreatin, Die
Starke, 23, 430-432
Leegwater, D. C. et al. (1972) Isolation and identification of an
O-(2-hydroxypropyl) maltose for the faeces of rats fed with
O-hydroxypropyl starch Carbohydr. Res., 25, 411-418
Leegwater, D. C. & Speek, A. J. (1972) Study on the faecal metabolites
of hydroxypropyl starch in the rat, Die Starke, 24, 373-374
Leegwater, D. C., de Groot, A. P. & Van Kalmthout-Kuyper, M. (1974)
The etiology of caecal enlargement in the rat, Fd. Cosmet.
Toxicol., 12, 687-698
Ragelis, E. P., Fisher, B. S. & Klimeck, B. A. (1966) J.O.A.C.,
49, 963
United States Food and Drug Administration (1969) Unpublished report,
submitted to WHO
Wesley, F., Rourke, B. & Darbishire, O. (1965) J. Fd. Sci., 30,
1037