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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given (no data on test substance purity, sick volunteers (patients with chronic disease were included in the study design)).

Data source

Reference
Reference Type:
publication
Title:
The effect of feeding large amounts of emulsifiers polyoxyethylene (20) sorbitan monostearate (Tween 60) and sorbitan monostearate (Span 60) to humans
Author:
Waldstein, S.S. et al.
Year:
1954
Bibliographic source:
Am J Dig Dis 21/7: 181-185

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
repeated dose toxicity: oral
Principles of method if other than guideline:
The study was undertaken to evaluate the pharmacological effect of 2 emulsifying agents, Span 60 (the test substance) and Tween 60, in doses far larger than ingested normally through foods (6 g/person/day) for 28 days.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sorbitan monostearate (Span 60)

Method

Type of population:
other: patients of a chronic disease, old people´s infirmary and hospital personnel
Subjects:
- Number of subjects exposed: patients of a chronic disease, old people´s infirmary: 32 persons were given the test and 25 persons the placebo capsules; hospital personnel: 10 persons were given the test and 10 persons the placebo capsules
- Age: 35-70 (patients of a chronic disease, old people´s infirmary), 25-40 (hospital personnel)
- Known diseases: Besides the patients with the chronic disease, the infirmary patients had been institutionalized for care of a variety of diseases, notably cerebal degenerative disease, generalized arteriosclerosis, arthritis, neurologic disorders, or inactive pulmonary tuberculosis. The hospital personnel subjects were free from disease at the time of study
- Other: Infirmary patients were screened by clinical and laboratory examination to eliminate anyone with active, metabolically significant disease.
Route of exposure:
oral
Reason of exposure:
intentional
Details on exposure:
The test substance was administered in gelatin capsules at a dose of 0.5 g. Six of these capsules were given twice daily resulting in a daily dose of 6 g/day (corresponding to 100 mg/kg bw, based on the assumption of an average body weight of 60 kg). Placebo capsules containing corn oil and resembling the test capsules in size, shape, consistenxy and color were additionally given to a group of subjects.
Inititally, 9 patients were studied. Because of abnormalities in certain tests during observation, 7 additional patients were observed during ingestion of the test substance.
Examinations:
- Urine analysis: albumin (sulfosalicylic acid method), reducing susbtances (Clinitest tablets) and acetone (Acetest tablets)
- Haematology: hemoglobin, red blood cell count, white blood cell total and differential count, red cell fragility and hematocrit, total serum protein, serum albumin/globulin, cephalin-cholesterol flocculation, thymol/zinc sulfate/phenol/gamma globulin turbidity, total serum bilirubin, bromsulfophtalein (BSP), non-protein nitrogen, creatinine, blood urea nitrogen, total serum cholesterol
- Other: Laboratory examinations were done before, after 14 days of feeding and at the conclusion of the 28 day administration period.

Results and discussion

Clinical signs:
No specific complaint was registered and the physical findings remained unchanged in all subjects.
Results of examinations:
- Urine analysis: 11 of the 32 patients tested and whose urines were albumin-free initially, showed a trace of albumin on the mid-term or final test. Two of the 25 patients who received placebo showed albuminuria. This was considered due to mild renal alterations, commonly found in elderly person.
Four patients showed glycosuria in the mid-term and final test; two of these were given a standard tolerance test: one had frank diabetes and the second an abnormal glucose tolerance test, both apparently antedating the study and having been missed during screening. However, to evaluate the test substance for a possible glycurosic effect, four non-diabetic patients in the fasting state were each fed 20 g of the test substance. None of them showed elevation of the blood sugar in the first four hours after ingestion of the material and none had reducing substance in the urine during the 24 hour periods before and after ingestion.
The Acetest remained negative in the subjects receiving the test substance, except for one patient who was a diabetic.

- Haematology: There were no significant changes in hemoglobin content, hematocrit, red cell count or red cell fragility in any patient studied. Two patients had leucocytosis (in one the count returned to normal by the final test) and one had a leucopenia of 3500 WBC/cu. mm. on the final count. One of the patients who received placebo also had leucopenia of 3500 WBC/cu. mm. on the final count.
The initially tested patients developed no significant abnormalities in cephalin-cholesterol flocculation, thymol/zinc sulfate turbidity, serum cholesterol, cholesterol esters, and serum creatinine. Therefore, except for zinc sulfate turbidity, these tests were not done on the subsequent patients given the test substance because of the constant normality. Zinc sulfate turbidity was above normal in the placebo and test groups during the observation period. Similarly, phenol turbidity and gamma globulin turbidity were tested and the percentage of abnormal values was of the same order in patients who received placebos as in those who received the test substance.
One patient had a slightly elevated total serum bilirubin on one determination which had returned to normal by the next determination.
There were no significant differences in serum non-protein nitrogen or in blood urea nitrogen in the test and placebo group.

- Other: Since bromosulfophthalein (BSP) retention was abnormal in one-third of patients who received either the test substance or Tween 60 (not further specified) on the mid-term or final test and only one of nine patients who received the placebo showed an abnormal result, an additional test on the BSP retention was performed with 16 patients receiving the test substance. None of these showed abnormal BSP retention at any time during observation or showed an elevated temperature at the time of testing. Serum phospholipids were determined and no significant change was noted in the levels before or after administration of test substance. Two additional normal persons were observed over a two week period without receiving any kind of test substance and while free of disease. Initially, they had BSP retentions of 3 and 2.5% (less than 6% as limit of normal) but on re-testing two weeks later showed abnormal values of 7 and 10%, respectively. Therefore, the variations found in the BSP in the first group of patients were believed to be false positive reactions not related to the substances ingested.

Applicant's summary and conclusion

Conclusions:
Based on the study design and the methods used, ingestions of 6 g test substance/day/person (corresponding to 100 mg/kg bw, based on the assumption of an average body weight of 60 kg) for 28 days had no deleterious effect to humans.