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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
Prior to 1960
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted prior to GLP and test guidelines, but sufficient data is available for interpretation of results

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Test rats were fed for 30 and 45 wk on a purified diet containing 9% PGPR plus 1.0% groundnut oil. Control animals were fed either 10% or 1.0% groundnut oil. During these safety tests, special studies were undertaken to show that PGPR acted as a nutrient and its digestion was comparable to edible fats
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
not specified
Details on test material:
PGPR is prepared in four stages: preparation of the castor oil fatty acids, condensation of the castor oil fatty acids, preparation of polyglycerol and partial esterification of the condensed castor oil fatty acids with polyglycerol.

The castor oil fatty acids are prepared by hydrolysing castor oil with water and steam at 400 psi pressure without any added catalyst after which the resulting fatty acids are freed from glycerol by water washing. Castor oil contains as its main fatty acid component ricinoleic acid (80–90%), and, it is this fatty acid which is important in the condensation reaction. Other fatty acids present are oleic acid (3–8%), linoleic acid (3–7%) and stearic acid (0–2%).

Fatty acid condensation is brought about by heating the castor oil fatty acids at elevated temperatures under vacuum and in an atmosphere of carbon dioxide to prevent oxidation. Samples are taken at regular intervals and tested for their free fatty acid content until an acid value of 35.0 is achieved. This acid value is equivalent to an average of about five fatty acid residues per molecule of the condensed product. During the condensation phase, ricinoleic acid may react in a number of ways as shown in Fig. 1. Simple linear esterification is the desired reaction but cyclic esterification, which is a chain terminating process, is theoretically possible. However, no evidence was found for the presence of this type of cyclic material in the condensed castor oil fatty acids. Dehydration is also possible, but occurs to only a small extent.

The preparation of the polyglycerol is achieved by heating glycerol to temperatures above 200°C in the presence of a small amount of alkali (potassium hydroxide). In this step, two or more molecules of glycerol condense with a loss of water and the formation of an ether linkage between the glycerol molecules. Carbon dioxide is bubbled through the reaction vessel to prevent oxidation, and unchanged glycerol is removed by distillation at the end of the reaction. The process is controlled by monitoring the rise in the refractive index. The result is a mixture of polyglycerols containing varying numbers of glycerol residues. As the 1- and 3-hydroxy groups of glycerol are more reactive than the 2-hydroxy group, the polyglycerols formed are predominantly straight-chain.

In addition, small amounts of cyclic by-products may be formed in the reaction mixture as a result of condensation between the 1-hydroxy group of one glycerol molecule and the 2-hydroxy group of another. The cyclic diglycerol product is a solid (m.p. 96°C), and is present at 4% in the polyglycerol or 0.4% in PGPR.

The final stage of the preparation involves heating an appropriate amount of polyglycerol with the condensed castor oil fatty acids. The reaction takes place immediately following the preparation of the latter and in the same vessel while the charge is still hot. The esterification conditions are the same as those for fatty acid condensation. The process is continued until a sample withdrawn from the reaction mixture is found to have a suitable acid value. The major components have the general structure shown in Fig. 2(C), where the average value of n is about 3. R1, R2 and R3 each may be hydrogen or a linear condensation product of ricinoleic acid with itself, as in Fig. 2(D) with n being on average between 5 and 8.

The JECFA specification for PGPR states that “the polyglycerol moiety shall be composed of not less than 75 percent of the di-, tri- and tetraglycerols and shall contain not more than 10 percent of polyglycerols equal to or higher than heptaglycerol” (FAO, 1992).

PGPR is specified further by the following:Hydroxyl value 85–100Acid value 2.0 max.Iodine value 80–90Refractive index at 65°C 1.4635–1.4665


Test animals

Species:
rat
Strain:
other: No data. However based on carcinogenicity study, probably were Colworth Wistar rats.
Sex:
male/female
Details on test animals and environmental conditions:
Entire study is described with results in two paragraphs in publication. See below.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
One group of control rats were fed 1.0% groundnut oil in their diet while the other group was fed 10% groundnut oil in their diet. Treated rats were fed 9% PGPR/1% groundnut oil.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data.
Duration of treatment / exposure:
Entire study is described with results in two paragraphs in publication. See below.
Frequency of treatment:
Entire study is described with results in two paragraphs in publication. See below.
Doses / concentrations
Remarks:
Doses / Concentrations:
0 and 9% PGPR
Basis:
nominal in diet
No. of animals per sex per dose:
Entire study is described with results in two paragraphs in publication. See below.
Control animals:
yes
Details on study design:
Entire study is described with results in two paragraphs in publication. See below.
Positive control:
No data.

Examinations

Observations and examinations performed and frequency:
Body weight, food and water consumption were recorded.
Sacrifice and pathology:
Entire study is described with results in two paragraphs in publication. See below.
Other examinations:
Entire study is described with results in two paragraphs in publication. See below.
Statistics:
No data.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increased liver weights
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See overall remarks which report that the liver changes are due to hypertrophy.
Histopathological findings: neoplastic:
not specified
Details on results:
During wk 5 of the 30-wk study, the rats fed 1.0% groundnut oil were fed no fat in their diet to measure endogenous fat excretion. The other rats continued on their diets containing 9% PGPR/1% groundnut oil or 10% groundnut oil. Faeces were collected for 7 days and analysed for fat. Comparison of fat intake with faecal fat excretion corrected for endogenous fat excretion showed that the digestibility of PGPR was 98.0%. This is nearly equivalent to that of groundnut oil alone, which was 99.8% for the diet containing 10% groundnut oil. Furthermore, when food was restricted for a period of 17 days and then restored ad lib., the energy restricted rats fed PGPR regained the lost body weight in an identical manner to rats fed groundnut oil. Analysis of the carcass and liver for total fat and free fatty acid contents demonstrated that body composition was similar to that of rats fed groundnut oil in their diet. Liver vitamin A values were also similar, indicating that PGPR had no effect on the absorption or utilization of vitamin A. PGPR did not affect the in vitro lipase digestion of groundnut oil, and while PGPR itself did not produce a plasma lipaemia after ingestion, the feeding of 9% PGPR with 9% groundnut oil had no effect on the lipaemia produced by the groundnut oil or on the rate of clearing of this lipaemia.

When rats were fed a purified diet containing 9% PGPR (plus 1% groundnut oil) in feeding trials of 30 or 45 wk duration, no adverse effects were observed on growth, food and water consumption and food utilization compared with rats fed a diet containing 10% groundnut oil. Haematological parameters such as haemoglobin level, haematocrit, erythrocyte count, prothrombin time and red cell fragility were not affected by feeding PGPR. Similarly, PGPR had no effect on the weights of kidneys, spleen, testes, adrenals and pituitary. The livers of rats fed PGPR in the 45-wk test, but not the 30-wk study, were significantly heavier at autopsy. Liver weights in this study were probably affected by the feeding of 18% PGPR prior to killing to see whether PGPR induced a lipaemia

Effect levels

Remarks on result:
not determinable
Remarks:
liver changes are due to hypertrophy

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Entire study is described with results in two paragraphs in publication. See above.

Applicant's summary and conclusion

Conclusions:
Liver hypertrophy was observed in rats (and mice) fed high doses of PGPR in the diet.
Executive summary:

Rats were fed up to 9% PGPR in the diet for 30 or 45 weeks. Liver hypertrophy was noted in rats (and mice) fed high doses PGPR in the diet.