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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication

Data source

Reference
Reference Type:
publication
Title:
Repeated dose oral toxicity study of the test chemical
Author:
Fitzhugh et al
Year:
1959
Bibliographic source:
Toxicology And Applied Pharmacology

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sorbitan monostearate, ethoxylated
EC Number:
500-020-4
EC Name:
Sorbitan monostearate, ethoxylated
Cas Number:
9005-67-8
Molecular formula:
C64-H126-O26 Unspecified
IUPAC Name:
Sorbitan monostearate, ethoxylated
Details on test material:
- Name of test material (as cited in study report): Tween 60
- Molecular formula (if other than submission substance): C64H126O26
- Molecular weight (if other than submission substance): 606.8318 g/mol
- Substance type: Organic
- Physical state: No data
- Impurities (identity and concentrations): No data

Test animals

Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: 40-50 g
- Fasting period before study:
- Housing: No data
- Diet (e.g. ad libitum): Ground commercial rat biscuits ad libitum
- Water (e.g. ad libitum): Water ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:
oral: feed
Details on route of administration:
No data
Vehicle:
other: Feed
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose level 0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day)

DIET PREPARATION
- Rate of preparation of diet (frequency): All diets were prepared in quantities approximating a 2-week supply
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water):Feed
- Concentration in vehicle: 0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day)
No. of animals per sex per dose:
0 mg/Kg/day: 12 males and 12 females
1000 mg/Kg/day: 12 males and 12 females
2500 mg/Kg/day: 12 males and 12 females
5000 mg/Kg/day: 12 males and 12 females
12500 mg/Kg/day: 12 males and 12 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Frequently
- Cage side observations checked in table [No.?] were included. General physical condition and abnormalities, Moribund state of animals was also noted

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Twice during the test period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 animals/group
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, Organ weights and gross pathology
were recorded for all sacrificed animal

HISTOPATHOLOGY: Yes, organs and tissues were fixed in formalin solution for histopathologic study
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Diarrhea was apparent throughout life in rats fed the test chemical, severe at 25%, moderate at 10%, and slight at 5%. No diarrhea was notes at 2% dose level.
Mortality:
no mortality observed
Description (incidence):
No effects were noted on survival of animals
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Average weight gain was calculated after 12 weeks on the diets to measure the effect on the early and rapid growth, and again after one year on the diet. Significant growth depression occurred in some groups at the 25% feeding level but in none at 10% or below. Adverse effects were more pronounced in males than in females. The inferior weight gain shown by male rats on test chemical was statistically significant only at the 12-week period.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Early growth depression in males fed 25% of the test chemical was accompanied by reduced food efficiency.
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Hematology studies showed normal values for hemoglobin, red and white blood cells, and differential counts for all groups.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Most animals on the highest emulsifier dosage had livers which were enlarged and more friable than normal. No significant liver enlargement occurred in rats at lower dosages.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
With the test chemical treatment, cecal enlargement was moderate at the 25% level and to a lesser degree at the 10% level. The increased size of the cecum was obvious at autopsy and the weight of the wall also proved to be greater for the test animals (mean of four representative ceca at the 25% level was 5.29 g) than for the controls (mean 3.59 g).
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Increased hepatic cell vacuolation at 25% was less-not enough to be a distinct difference. With the test chemical, the enlarged ceca were normal microscopically.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effects were noted at the mentioned dose level

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table: Survival rate of rats treated for 2 years

No. of animals

Dietary level (%)

No .of survivors

Survival rate (%)

24

0

12

50.0

24

2

15

62.5

24

5

14

58.3

24

10

12

50.0

24

25

9

37.5

 

Table: Food Efficiency Of Diets Containing 25% Stearate Emulsifiers Fed To Rats For 12 Weeks

Dose level (%)

No. of animals

Sex

Average gain weight (g)

Average food intake (g)

Food efficiency (g et gain/100 g food)

0

12

M

313.2±15.3

1752

17.8

 

12

F

178.6±9.8

1269

14.1

25

12

M

271.6±6.3

1589

17.1

 

12

F

175.7±5.1

1485

11.9

 

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed for 2 years.
Executive summary:

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using Osborne Mendel rats. The test chemical was mixed with feed at dose level of0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day) for 2 years. During the study, the animals were observed for mortality, morbidity, clinical signs, boody weight and organ weight changes, hematology, gross pathology and histopathology. Survival was unaltered by chemical treatment.Diarrhea was apparent throughout life in rats fed the test chemical, severe at 25%, moderate at 10%, and slight at 5%. No diarrhea was notes at 2% dose level. Average weight gain was calculated after 12 weeks on the diets to measure the effect on the early and rapid growth, and again after one year on the diet. Significant growth depression occurred in some groups at the 25% feeding level but in none at 10% or below. Adverse effects were more pronounced in males than in females. The inferior weight gain shown by male rats on the test chemical was statistically significant only at the 12-week period. Early growth depression in males fed 25% of the test chemical was accompanied by reduced food efficiency. Hematology studies showed normal values for hemoglobin, red and white blood cells, and differential counts for all groups. Most animals on the highest emulsifier dosage had livers which were enlarged and more friable than normal. No significant liver enlargement occurred in rats at lower dosages. With the test chemical treatment, cecal enlargement was moderate at the 25% level and to a lesser degree at the 10% level. The increased size of the cecum was obvious at autopsy and the weight of the wall also proved to be greater for the test animals (mean of four representative ceca at the 25% level was 5.29 g) than for the controls (mean 3.59 g). Increased hepatic cell vacuolation at 25% was less-not enough to be a distinct difference. With the test chemical, the enlarged ceca were normal microscopically. Based on the observations made, the no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed for 2 years.