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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (non-GLP, limited documentation, no opthalmoscopy and neurobehavioural examination, 15 animals/dose group, no NOAEL identified).

Data source

Reference
Reference Type:
publication
Title:
Short-term toxicity study of sorbitan monolaurate (Span 20) in rats
Author:
Cater, B.R. et al.
Year:
1978
Bibliographic source:
Food Cosmet Toxicol 16(6): 519-26

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
(non-GLP, limited documentation, no opthalmoscopy and neurobehavioural examination, 15 animals/dose group)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Physical state: oily liquid
- Analytical purity: approx. 95%
- Impurities (identity and concentrations): water (max. 1%), sulphated ash (max. 0.25%), arsenic (max. 3 ppm), lead (max. 10 ppm), copper (max. 50 ppm), zinc (max. 25 ppm)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: A. Tuck & Son, Rayleigh, Essex
- Housing: 5 per cage

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The animals were fed a diet (ground Spratts Laboratory Diet No.1) containing the test substance.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
continuously (via diet)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
2100, 4200, 8000 mg/kg bw/day
Basis:
other: mean intake of test compound, males
Remarks:
Doses / Concentrations:
2300, 4500, 8400 mg/kg bw/day
Basis:
other: mean intake of test compound, females
Remarks:
Doses / Concentrations:
2.5, 5.0, 10.0 %
Basis:
nominal in diet
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Details on study design:
The animals were weighed and the food and water intakes of each cage was measured weekly.

Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE :
- Food consumption for each cage was determined and mean daily diet consumption calculated as g food/kg body weight/day

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 2, 6, and 13 weeks
- Anaesthetic used for blood collection: Yes (at 13 weeks collection): barbiturate anaesthesia
- Animals fasted: no
- How many animals: all
- Parameters examined: haemoglobin, packed cell volume, counts of erythrocytes, reticulocytes and total and differential white blood cells

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 6 and 13 weeks of treatment (females: all parameter after 6 and 13 weeks, males: total protein, albumin only after 13 weeks)
- Animals fasted: no
- How many animals: all
- Parameters examined: total protein, albumin, activity of glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase and lactic dehydrogenase

URINALYSIS: Yes
- Time schedule for collection of urine: 6 h period during the final week
- Animals fasted: no
- Parameters examined: albumin, glucose, ketones, bile salts, blood
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
brain, pituitary, thyroid, heart, liver, spleen, kidneys, adrenal glands, gonads, stomach, small intestine, caecum

HISTOPATHOLOGY: Yes
brain, pituitary, thyroid, heart, liver, spleen, kidneys, adrenal glands, gonads, stomach, small intestine, caecum, lung, salivary gland, aortic arch, thymus, various lymph glands, urinary bladder, colon, rectum, pancreas, uterus, skeletal muscle
Other examinations:
Measurement of specific gravity and volume of urine:
6 h period of water deprivation
2 h period following a water load (25 ml/kg)
4 h period following a 16 h period of water deprivation
Statistics:
Student´s t-test for body and organ weights and White (1952) test for food consumption

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased body weights at 5 and 10%
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
lower food consumption
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
increase in mid dose group males, decrease in high dose females
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Hb, erythrocyte cound, reticulocyte counts changed
Clinical biochemistry findings:
no effects observed
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):
increased liver and kidney weights
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
increase of periportal fat at 5 and 10%
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No deaths or abnormal behaviour was seen.

BODY WEIGHT AND WEIGHT GAIN
Decreased body weights were seen in the 5 or 10% group after 48 h of start of treatment (-19 and -32%, respectively) and remained less until the end of the study (-19 and -27%, respectively), see Table 1. The effect was detectable, but less marked in the 2.5% group (statistically significant after 6-9 days of treatment, about 10%).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The average food intake was lower over the treatment period, related to the dietary concentration of the test substance (see Table 1).
Paired-feeding study:
Body weights of treated animals were lower than those of the pair-fed controls. The differences were less than with the ad. lib. controls.

HAEMATOLOGY
Haemoglobin concentration and packed cell volume was decreased in all groups and both sexes in a dose dependent manner beginning with the second week of the study period (see Table 2). Red blood cell counts were decreased at the lower treatment levels, but increased at the highest treatment level, beginning with week 6 in booth sexes. A tendency for increased reticulocyte counts and decrease in total leucocyte counts was seen in both sexes.

CLINICAL CHEMISTRY
Results were similar in the test and the control animals.

WATER CONSUMPTION AND COMPOUND INTAKE
An increase in mid dose group males and a decrease in high dose females was observed for water consumption over the hole study period.

URINALYSIS
There was a tendency for the treated male rats to produce less urine with a higher specific gravity.

ORGAN WEIGHTS
Absolute weights of brain, heart, parts of gastro-intestinal tract and testes were unchanged or decreased, but relative organ weight was increased in treated groups (see Table 3). Spleen weights were decreased, with unchanged relative organ weight. Absolute and relative liver weights in males and females were increased (10% group). Absolute kidney weights were increased (5, 10% group), relative kidney weights were increased in all dose groups.
Paired-feeding study:
Liver and kidney weights were significantly increased. Relative organ weights of those organs, as well as of heart and small intestine were increased.
HISTOPATHOLOGY: NON-NEOPLASTIC
Periportal vacuolation was observed in the livers in the highest dose group. An increase of periportal fat was determined in females (5, 10% group) and males (10% group). Early nephrosis was observed in test and control animals.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Due to the high dose levels administered, no NOAEL but only a LOAEL can be determined.
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
LOAEL
Effect level:
2 300 other: mg/kg bw/day: mean intake of test compound
Based on:
test mat.
Sex:
female
Basis for effect level:
other: effects on body weight, food consumption, haematology, organ weights and histopathology
Dose descriptor:
LOAEL
Effect level:
2 100 other: mg/kg bw/day: mean intake of test compound
Based on:
test mat.
Sex:
male
Basis for effect level:
other: effects on body weight, food consumption, haematology, organ weights and histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Mean data body weights and on food consumption and resulting intake of test substance

 

 

Body weight (g) at day

Food consumption (g/rat/day) at day

 

 

Diet

Dietary level (%)

0#

1

27

55

90

0#

1

27

55

90

Mean food consumption (g/rat/day)

Mean intake of test compound

Males

Control

0

86

93

263

371

432

13.3

14.5

21.3

22

18.9

20.2

0

Test substance

2.5

85

87

238**

332**

389**

10.7

13.3

19.2

19.4

17.5

18.5*

2.1

 

5

85

86

214***

294***

350***

9.6

10.1

16.4

18.7

17.8

16.9***

4.2

 

10

84

81**

179***

263***

316***

7.5

7.8

16

17.1

15.9

15.4***

8

Females

Control

 

69

75

176

221

250

10.5

11.7

15.7

16.3

13.7

15.3

0

Test substance

2.5

71

73

162**

205*

233

9.1

9.3

13.1

15.5

14.7

14.7

2.3

 

5

71

70*

152***

198**

225**

7.3

6.8

12.9

15.5

14.3

13.6*

4.5

 

10

71

68**

141***

172***

191***

4.6

5.9

11.7

12.8

12.3

11.8***

8.4

#: pretreatment value on day 1 of study

*p<0.05, **p<0.01, ***p<0.0001

Table 2: Mean haematological findings after 2, 6 or 13 weeks

                     

Leucocytes

 

 

 

 

 

 

 

 

Differential (%)

Sex and diet

Dietary level

Hb (g/100 mL)

PCV (%)

RBC (106/mm³)

Retics (% of RBC)

Total (103/mm³)

N

E

L

M

Week 2

Male

 

 

 

 

 

 

 

 

 

 

Control

0

14.4

44

6.7

3.4

6.7

11

1

87

1

Test substance

5

13.6*

41*

6.6

1.5**

5.6

12

1

86

1

 

10

13**

41*

7.5

4.4

5.5

14

1

84

1

Female

 

 

 

 

 

 

 

 

 

 

Control

0

14.7

44

7

1.9

5

16

1

82

1

Test substance

5

14.2

41*

6.7

1.1

3.9

11

0

88

1

 

10

13***

40**

6.3*

2.7

3.4

11

0

88

1

Week 6

Male

 

 

 

 

 

 

 

 

 

 

Control

0

15.6

47

7.2

1.2

5.3

11

1

87

1

Test substance

5

14**

42**

6.9

0.8*

5

8

0

91

1

 

10

13.2***

41**

8.5*

2.4**

4.4

14

1

84

1

Female

 

 

 

 

 

 

 

 

 

 

Control

0

15

44

7.1

0.7

5.3

13

1

85

1

Test substance

5

13.9***

41*

6.5*

0.6

4

12

2

85

1

 

10

14.2*

41

8*

1

4.4

12

0

88

0

Week 13

Male

 

 

 

 

 

 

 

 

 

 

Control

0

15.3

45

8

0.3

6

14

1

84

1

Test substance

2.5

15.2

44

7.2*

0.6

4.4**

18

1

80

1

 

2.5

14.2**

43**

7.1*

0.7*

4.6*

16

1

81

2

 

10

13.7***

41***

8.2

0.9*

4.8*

16

1

83

1

Female

 

 

 

 

 

 

 

 

 

 

Control

0

14.6

45

7

0.9**

3.7

17

1

81

1

Test substance

2.5

14.8

45

7.2

0.7

3.7

14

 

84

1

 

5

14**

42**

7

0.7

3.6

13

1

85

1

 

10

12.3***

39***

8.1**

0.8

4.2

15

1

82

2

*p<0.05, **p<0.01, ***p<0.0001

Hb: Haemoglobin, PCV: Packed cell volume, RBC: Red blood cells, Retics: Reticulocytes, N: Neutrophils, E: Eosinophils, L: Lymphocytes, M: Monocytes

Table 3: Mean relative organ weights (g/100g body weight) of rats feed the test diets after 13 weeks

Sex and diet

Dietary level

Brain

Heart

Liver

Kidneys

Adrenals#

Gonads$

Pituitary#

Thyroid#

Terminal body weight (g)

Male

 

 

 

 

 

 

 

 

 

 

Control

0

0.46

0.25

2.51

0.56

12.8

0.94

2.2

3.5

418

Test substance

2.5

0.51*

0.27

2.38

0.63***

15.9**

0.98

2.3

3.9

377**

 

5

0.55***

0.28

2.54

0.75***

15.7*

1.05

2.3

3.7

338***

 

10

0.6***

0.31***

3.67***

0.71***

14.5

1.15***

2.6*

4

305***

Female

 

 

 

 

 

 

 

 

 

 

Control

0

0.72

0.3

2.5

0.6

25.8

47.1

4.9

4.9

245

Test substance

2.5

0.78*

0.31

2.44

0.69***

26.5

48.5

4.8

4.5

227*

 

5

0.79*

0.32

2.67

0.88***

29

47.9

4.5

5.3

221**

 

10

0.9***

0.35***

4.39***

0.97***

25.7

50.4

4.3

5.6

190***

*p<0.05, **p<0.01, ***p<0.0001

#: Weights of this organs are express in mg/100 bw

$: Weights of female gonads are expressed in mg/100 g bw

Applicant's summary and conclusion