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Toxicological information

Carcinogenicity

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Description of key information

There are no data for polyglycerine. Data does exist for glycerine and the higher MW material. In the case of glycerine, the subchronic NOAEL was 8000-10,000 mg/kg bw based on the absence of treatment-related effects in high dose animals. In the case of the higher MW material, chronic toxicity/carcinogenicity data exists for polyglycerol polyricinoleate (PGPR). PGPR has been shown to be metabolized in the GI tract releasing polyglycerine(called Polyglycerine-Heavy in Justification document) which is excreted unchanged in the urine (diglycerine and triglycerine) and feces (higher MW glycerines) (Detailed in Sections 7.1.1 and 13). No carcinogenic effect was found for PGPR after feeding 5% to rats for 2 yr.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: 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 1970
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to guideline and/or standard method but was non-GLP.
Qualifier:
according to
Guideline:
other: Ministry of Health (1960) Carcinogenic risks in food additives and pesticides. Monthly Bulletin of the Ministry of Health 19, 108–112
Deviations:
not specified
Principles of method if other than guideline:
The studies carried out included a 2-yr rat feeding study in Colworth Wistar rats. The studies were conducted in the 1960s in accordance with guidelines and standards in operation at the time (Ministry of Health, 1960)
GLP compliance:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
120 Colworth Wistar rats (60 of each sex obtained from the breeding facility at the Unilever Colworth Laboratory, Sharnbrook, Bedford, UK) were randomly divided at 32–42 days old into test and control groups, each of 30 male and 30 female animals. The rats were housed in individual cages.

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Test animals were fed a diet containing 2% PGPR for the first 10 wk and then 5% PGPR for the remainder of the 2-yr period. Control animals were fed the same diet except that groundnut oil replaced the PGPR. The composition of the purified diets which were fed ad lib. for 2 yr is shown in Table 1a and Table 1b. Water was also provided ad lib. to the rats.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data.
Duration of treatment / exposure:
continuous for two years
Frequency of treatment:
continuous in diet
Post exposure period:
Not applicable
Remarks:
Doses / Concentrations:
diet containing 2% PGPR for the first 10 wk and then 5% PGPR for the remainder of the 2-yr period
Basis:
nominal in diet
No. of animals per sex per dose:
30 males and 30 females/dose level
Control animals:
other: groundnut oil replaced the PGPR
Details on study design:
Test animals were fed a diet containing 2% PGPR for the first 10 wk and then 5% PGPR for the remainder of the 2-yr period. Control animals were fed the same diet except that groundnut oil replaced the PGPR. Blood, collected after 80 wk from four rats of each sex fed PGPR or the control diet, and on all surviving animals at study termination was analysed for erythrocyte and leucocyte counts, haemoglobin concentrations and value, red cell fragility and prothrombin time. Each animal was subjected to gross examination at autopsy. The following organs were weighed and the organ/body weight ratios determined: adrenals, heart, kidney, spleen, liver, testes, thyroid and pituitary. These organs, together with the lung, ovary, uterus, thymus, stomach, intestine, caecum, bladder, lymph nodes, skin, mammary gland, tongue and any macroscopic abnormality were removed, fixed and processed for histological examination
Positive control:
No data.
Observations and examinations performed and frequency:
Animals were observed daily for clinical signs of toxicity or changes in behaviour, and were weighed weekly. Food consumption was measured three times weekly and evaluated as a weekly amount.
Sacrifice and pathology:
Liver function was examined after 84 and 103 wk using the bromosulfothalein excretion test. Kidney function was assessed at the same times by measuring urine concentration. Blood was collected by cardiac puncture under ether anaesthesia after 80 wk from four rats of each sex fed PGPR or the control diet, and on all surviving animals at study termination. Blood samples were analysed for erythrocyte and leucocyte counts, haemoglobin concentrations and value, red cell fragility and prothrombin time. Each animal was subjected to gross examination at autopsy. The following organs were weighed and the organ/body weight ratios determined: adrenals, heart, kidney, spleen, liver, testes, thyroid and pituitary. These organs, together with the lung, ovary, uterus, thymus, stomach, intestine, caecum, bladder, lymph nodes, skin, mammary gland, tongue and any macroscopic abnormality were removed, fixed and processed for histological examination.

Other examinations:
No additional information available
Statistics:
All records were examined separately for each sex by analysis of variance to assess the significance of any inter-group differences. Organ weights were also analysed if justified by an analysis of covariance on final body weight.

In the analysis of variance, the F-ratio test was used to test whether the treatments differed. Student's t-tests were then used to compare every treatment mean individually against the control.
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):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
limited tests reported
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
kidneys from male and female rats and livers from female (but not male) rats fed PGPR were heavier than those fed the control diet.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Rats in both treatment and control groups occasionally showed clinical signs of respiratory disease, which in some cases was accompanied by loss of body weight and reduced food consumption. The incidence of respiratory disease was most evident from wk 50 onwards. Bronchiectasis and emphysema were the main cause of death among animals in both test and control groups. The incidence of respiratory disease was comparable between treatment and control groups.

No statistical difference (P=0.05) was found for survival between PGPR-fed and control rats when those dying from non-treatment-related factors (death during blood sampling and from intestinal obstruction—hair ball) were excluded (survival figures are shown in Table 3).

No treatment-related adverse effects were found for body weight and food consumption (Table 4 and Table 5). Liver function tests (bromosulfothalein excretion) and blood analyses revealed no signs of treatment-related effects. Urinalysis revealed no difference in specific gravity at wk 84 but a significantly lower specific gravity for urine from PGPR fed rats at wk 103, but all values fell within the historical value range (data not shown). Organ weight measurements showed that kidneys from male and female rats and livers from female (but not male) rats fed PGPR were heavier than those fed the control diet (Table 6).

Histological assessment of tissues revealed no treatment-related effect (data not shown). The incidence of tumours was comparable between control and treated rats (Table 7).



Relevance of carcinogenic effects / potential:
Although this is a study conducted in the 1960s, there was no evidence of a carcinogenic effect observed in rats fed 5% polyglycerol polyricinoleate in the diet.
Dose descriptor:
NOEL
Effect level:
5 other: % in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no carcinogenic effects noted in rats fed 5% in the diet.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Table 3.Rat survival after 104 wk

Sex PGPR diet Control purified diet
Male 18/30 (60.0%) 23/30 (76.7%)
Female 18/30 (60.0%) 21/30 (70.0%)
Total 36/60 (60.0%) 44/60 (73.3%)

Table 4.Mean body weight gains of rats fed for 104 wk on PGPR or control diets

Mean body weight gains (g)
Males Females
Wk PGPR diet Purified diet (control) PGPR diet Purified diet (control)
0–3 78.7 79.7 44.3 48.1
3–9 95.0 90.7 52.1 49.8
9–20 48.9 57.3 27.2 30.1
20–60 60.8 53.2 17.1 16.5
60–104 −19.1 −11.8 13.6 27.9
0–104 264.3 269.1 154.3 172.4

Table 5.Mean total food consumption by rats fed for 104 wk on PGPR or control diets

Mean total food consumption (g)
Males Females
Wk PGPR diet Purified diet (control) PGPR diet Purified diet (control)
0–3 281.9 279.9 230.8 246.3
3–9 660.2 644.1 508.5 509.3
9–20 1255.3 1264.0 936.3 957.2
20–60 4060.8 3968.5 3140.9 3187.5
60–104 4595.6 4407.3 3699.6 3831.4
0–104 10853.8 10563.8 8516.1 8731.7

Table 6.Mean organ weights for rats fed for 104 wk on PGPR and control diets

Mean organ weight
Absolute weight (g±SD) Weight (g/100 g rat body wt (±SD)
Males Females Males Females
Diet PGPR Purified control PGPR Purified control PGPR Purified control PGPR Purified control
Liver 12.18 (1.84) 11.45 (1.61) 9.15a(2.72) 8.67 (1.72) 3.38 (0.58) 3.24 (0.32) 3.92a(0.85) 3.48 (0.47)
Kidneys 3.59a(0.61) 3.19 (0.45) 2.52a(0.50) 2.37 (0.34) 1.00a(0.17) 0.90 (0.13) 1.08a(0.20) 0.95 (0.14)
Heart 1.39 (0.31) 1.30 (0.23) 1.00 (0.16) 1.05 (0.23) 0.38 (0.09) 0.367 (0.09) 0.43 (0.08) 0.42 (0.09)
Spleen 0.95 (0.37) 0.849 (0.28) 0.60 (0.13) 0.65 (0.180) 0.26 (0.11) 0.237 (0.10) 0.26 (0.05) 0.26 (0.07)
Pituitary 0.010 (0.001) 0.008 (0.004) 0.010 (0.044) 0.011 (0.033) 0.0027 (0.001) 0.002 (0.001) 0.004 (0.001) 0.004 (0.002)
Thyroid 0.028 (0.005) 0.029 (0.007) 0.023 (0.005) 0.024 (0.008) 0.0079 (0.008) 0.008 (0.002) 0.010 (0.002) 0.009 (0.003)
Adrenals 0.081 (0.014) 0.078 (0.012) 0.091 (0.026) 0.098 (0.016) 0.022 (0.004) 0.022 (0.004) 0.039 (0.010) 0.0394 (0.007)
Testes 2.85 (0.71) 2.56 (0.86) 0.790 (0.192) 0.724 (0.26)

a Significantly different from control (P=0.05).

Table 7.Tumour incidence of rats fed PGPR or control diet

Animals killed after 104 wk Animals dying during test
Males Females Males Females
Total no. of rats examined PGPR Control PGPR Control PGPR Control PGPR Control
18 23 18 21 12 7 12 9
Tumour incidence
Total primary tumours 9(50.0%) 9(39.1%) 8(44.4%) 11(52.4%) 1(8.3%) 2(28.6%) 4(33.3%) 2(22.2%)
Rats with one tumour 6 7 6 6 1 2 2 2
Rats with multiple tumours 1 1 1 2 0 0 1 0
Tumour types
(a) Uterus
 Adenocarcinoma 1 0 0 0
 Fibroma 0 1 1 0
(b) Thymus
 Thymoma 0 1 0 1 0 0 2 0
(c) Thyroid
 Adenoma  4  5  2  3  0  0  0  0
 (d) Pituitary                
 Adenoma  3  2  5  6  1  1  1  0
 (e) Testis                
 Adenoma (Leydig cell)  2  0  --  --  0  0  --  --
 (f) Mesentery                
 Lipoma  0  1  0  0  0  0  0  0
 (g) Stomach                
 Squamous cell papilloma  0  0  0  0  0  1  0  0
 (h) Tongue                
 Sarcoma  0  0  0  0  0  0  0  1
 (i) Subcutaneous tissue                
 Fibrosarcoma  0  0  0  0  0  0  0  1
Conclusions:
There was no evidence of a carcinogenic effect observed in rats fed 5% polyglycerol polyricinoleate in the diet. Organ weight analysis revealed an increase in liver and kidney weight in both male and female rats
Executive summary:

The carcinogenic potential of the food emulsifier ADMUL WOL brand of polyglycerol polyricinoleate (PGPR) was evaluated in rats

and mice. Groups of 60 male and 60 female rats were given purified diets containing 5% of either PGPR or groundnut oil for 2 years.

No carcinogenic effect of PGPR was observed. In addition, dietary PGPR had no adverse effect on growth, food consumption,

longevity and haematology. Organ weight analysis revealed an increase in liver and kidney weight in both male and female rats.

Histological analysis of tissues revealed no treatment related adverse effects.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no data for polyglycerine. Data do exist for glycerine or the higher MW material. In the case of glycerine, the chronic NOAEL was 8000-10,000 mg/kg bw based on the absence of treatment-related effects in high dose animals. In the case of the higher MW material, chronic toxicity/carcinogenicity data exist for polyglycerol polyricinoleate (PGPR). PGPR has been shown to be metabolized in the GI tract releasing polyglycerine (called Polyglycerine-Heavy in Justification document) which is excreted unchanged in the urine (diglycerine and triglycerine) and feces (higher MW glycerines) (Detailed in Sections 7.1.1 and 13). No carcinogenic effect was found for PGPR after feeding 5% to rats for 2 yr. In addition, PGPR had no adverse effect on growth, food consumption, survival, haematology or histological appearance of tissues. The changes in weight of liver and kidneys in PGPR-fed animals were consistent with those seen in previous studies and considered to be a result of metabolic compensation in response to the high level of PGPR ingested. As noted in Section 7.5, castor oil, used in the preparation of PGPR, likewise affects the liver probably due to an adaptive hypertrophy, without toxic damage, through the need to metabolize ricinoleic acid. Thus the subchronic effects observed with PGPR are believed to not be due to polyglycerine but rather attributed solely to the polyricinoleate portion of the molecule.


Justification for selection of carcinogenicity via oral route endpoint:
Data from polyglycerol (as part of polyglycerol polyricinoleate).

Justification for classification or non-classification

There is no justification for classification based on data from available studies.


Route: .live2