Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 1971
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1971

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:
Administration of doses
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Housing and feeding conditions:
The animals were housed in individual cages for an acclimatization time of 14 days.
The temperature of the experimental animal room was 22°C (+-1°C). The relative humidity was 45-55%. Lighting was artificial, the sequence was 12 hours light, 12 hours dark. Food and water was provided at discretion.
For the test, the animals were divided into 4 groups of 10 male and 10 female animals each.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The test substance was administered as 1 and 10% aqueous solution.
Duration of treatment / exposure:
The treatment/exposure took place over a period of three months.
Frequency of treatment:
The aqueous solution was administered weekly on five consecutive days.
Doses / concentrationsopen allclose all
Dose / conc.:
2 other: mL aqua dest./animal
Remarks:
control group
Dose / conc.:
20 mg/kg bw (total dose)
Remarks:
group I
Dose / conc.:
50 mg/kg bw (total dose)
Remarks:
group II
Dose / conc.:
200 mg/kg bw (total dose)
Remarks:
group III
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
The dose setting was determined by a pretest over four weeks.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Between the control animals and the two lower limit test groups no significant difference occurred. These animals showed straight and shiny hair, normal feces and a healthy total habitus.
The male animals of the highest test group showed an unkempt coat (yellowish brown and a bit shaggy) already after 6 weeks of treatment. In contrast, the female animals showed no difference to the control group.
Mortality:
mortality observed, treatment-related
Description (incidence):
In the control and the two lower limit test groups no mortalities occurred. In the upper dosage group 4 of 20 animals died during the whole test duration (3 males and 1 female).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
For the male animals, a linear dosage-related trend within the group could be observed. An increase of the dosage led to a reduced body weight.
For the female animals, a slightly but not clear dosage-related body weight change could be observed. The growth pattern of the test groups are within the range of the control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Between the control and the two lower limit test groups no significant difference occurred during the whole test duration.
The male animals of the highest test group showed a reduced feed intake in all 4-week phase during the whole test duration.
In contrast, the female animals showed no significant difference to the control group.
Food efficiency:
no effects observed
Description (incidence and severity):
During the whole test duration no significant difference between the control and the test groups occurred. All values were within the biological range.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Under the mentioned conditions no significant difference between the control and the test groups occurred. The water consumption was within the normal fluctuation range of the used rat strain.
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
During the whole test duration and under the mentioned conditions no statistical significant difference, nor dosage-related group trends occurred between the control and the test groups. All values were within the physiological range.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Alkaline phosphatase:
During the whole test duration and under the mentioned conditions no statistical significant difference, nor dosage-related group trends occurred between the control and the test groups. All values were within the physiological range.

Serum glutamate-pyruvate transaminase (SGPT):
During the whole test duration and under the mentioned conditions no statistical significant difference, nor dosage-related group trends occurred between the control and the test groups. All values were within the physiological range.
Urinalysis findings:
no effects observed
Description (incidence and severity):
During the whole test duration, no significant difference of the observed values occurred between the control and the test groups. All observed and measured values were within the physiological range.

Blood urea: Under the given test conditions no statistical significant differences nor dosage-related group trends occurred in comparison between the control and test groups. All values were within the physiological range.
Behaviour (functional findings):
not specified
Immunological findings:
effects observed, treatment-related
Description (incidence and severity):
Blood values: Under the given test conditions no statistical significant differences nor dosage-related group trends occurred in comparison between the control and test groups. All values were within the physiological range.

Erythrocytes: Under the given test conditions no statistical significant differences nor dosage-related group trends occurred in comparison between the control and test groups. All values were within the physiological range.

Reticulocytes: Under the given test conditions no statistical significant differences nor dosage-related group trends occurred in comparison between the control and test groups. All values were within the physiological range.

Glucose: Under the given test conditions no significant differences could be determined in comparison between the control and two lower dosage test groups. In the second 4 week phase and at the end of the test the highest dosage group showed increased values in comparison to the control.

Prothrombin time: Under the given test conditions no statistical significant differences nor dosage-related group trends occurred in comparison between the control and test groups. All values were within the physiological range.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Between the control and the test group neither for the males nor for the females significant differences could be observed. All weights were within the biological range.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the test, in the killed animals no test specific effects could be macroscopic pathological observed in the cranial, chest or abdominal cavity.
In the four above mentioned dead animals advanced autolysis could be observed.
Neuropathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Cerebrum: focal fibrosis of the leptomeninges in low-grade to moderate form in two animals from the lowest dosage group; focal satellitosis in one animal from the lowest dosage group.

Cerebellum: focal fibrosis of the leptomeninges in low-grade to moderate form in two animals from the lowest dosage group, in one animal of the control group and in one animal of the highest dosage group.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Thyroid: missing in one animal from the highest dosage group.

Lung: interstitial pneumonia in low-grade to moderate form combined with atelectasis in almost all control and test animals.

Heart: minimally focal lymphofibroblastic foci in one animal of the control group, in one animal of the lowest dosage group and in one animal of the highest dosage group. Discoloration of fat at the heart: diffuse simple fine droplets fatty degeneration in moderate form in one animal of the highest dosage group was observed.

Colon: focal lymphatic activation in moderate form in three animals of the lowest, in two animals of the middle and in four animals of the highest dosage group.

Liver: Activation of the mononuclear phagocyte system: low-grade form in four animals of the control group, in two animals of the lowest dosage group and in one animal of the middle group; in moderate form in one animal of the control group, in one animal of the middle group and in two animals of the highest dosage group. Polymorphism of the liver cell nucleus in one animal of the middle group. Periportal lymphocytic infiltrate in low-grade to moderate form in most of the animals of the control and test groups. Discoloration of fat at the liver: individual cell fatty degeneration: in low-grad form in four animals of the control group, in five animals of the lowest dosage group, in four animals of the middle dosage group and in four animals of the highest dosage group; in moderate form in one animal of the control group, in one animal of the lowest dosage group, in four animals of the middle dosage group and in one animal of the highest dosage group. Diffuse fatty degeneration in moderate form combined with stellate cell fatty degeneration in one animal of the lowest dosage group, in two animals of the middle dosage group and in two animals of the highest dosage group.

Kidney: no effects observed

Adrenal glands: no effects observed

Spleen: no effects observed

Gonads:
testicles: no effects observed
epididymis: no effects observed
ovary: no effects observed
uterus: low-grade lymphocytic endometritis with the involvement of less leukocytes in one animal of the control, one of the lowest dosage and one of the highest dosage group. Infiltration of eosinophils in a low-grade form were observed in two animals of the middle and two animals of the highest dosage.
Histopathological findings: neoplastic:
no effects observed
Details on results:
The lung change in form of interstitial pneumonia occur in that form frequently as a rat specific alteration. In addition, the lymphofibroblastic infiltrates in the hearts occur in this form frequently in rats. They were observed in control as well as in test animals.
The tendency of fibrosis in the soft meninges in the brain and in the cerebellum of single control and test animals can be consider as individual findings. These findings can be also often observed in laboratory animals. The diffuse simple fine droplets fatty degeneration in moderate form in one animal of the highest dosage group as well as the unincisive endometritis of a few control and test animals can be evaluated as incidental findings. The infiltration of eosinophils in two animals respectively of the middle and highest dosage group can be evaluated in the same way.
The low-grade to moderate form of the activation of the mononuclear phagocyte system affected in almost equal frequency control and test animals. In addition, the individual cell fatty degeneration is relative evenly distributed on all groups.
In contrast, the diffuse fatty degeneration in exclusively moderate form, which is accompanied by fat deposits in stellate cells, in animals of the three test groups (1 time lowest dosage group, 2 times middle dosage group and 2 times highest dosage group) is remarkable. If it can be considered as incidental findings, it still should take into account, that this fatty degeneration hast to be interpreted as an expression of a special liver strain during the test.
In addition, lymphatic activation in moderate form could be only observed in animals of the test groups (3 times lowest dosage group, 2 times middle dosage group and 4 times highest dosage group). Even in this case, it can be an expression of resorption strain of the test animals.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
food efficiency
water consumption and compound intake
haematology
clinical biochemistry
urinalysis
immunology
organ weights and organ / body weight ratios
gross pathology
neuropathology
histopathology: non-neoplastic
histopathology: neoplastic
Key result
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
food consumption and compound intake
other: blood sugar

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
During the study, some effects could be observed which do not justify classification. This concerns the clinical observations, small changes in bodyweight gain and the food consumption. The significant reduced weight gain and feed intake as well as the increased blood sugar and the mortality in the 200 mg/kg group has to be taken into account. As the LOAEL value is over the guidance value of 100 mg/kg bw/day no STOT RE category are met.

Histology: Unambiguous substance- and test-related findings could not be determined. The exclusive occurrence of lymphatic activation in the colon of one third of the test animals as well as a diffuse fatty degeneration together with fat deposits in stellate cells in two animals of the three test groups respectively can be evaluated as an expression of the metabolic strain by the test substance. In addition, these observations do not justify classification.
Executive summary:

The test substance 2 -lauroyloxyethyltrimethylammonium chloride was administered orally to rat over three month in the following dosages: 20, 50 and 200 mg/kg.

Under the mentioned conditions, it was identified:

1. The test substance effected at 200 mg/kg the clinical signs of the male rats.

2. The test substance induced in the 200 mg/kg group 20 % mortality.

3. The test substance induced in the males of the 200 mg/kg group significant reduced weight gain.

4. The test substance led to a significant reduced feed intake of the males of the 200 mg/kg group, but without influencing the feed effectiveness.

5. The test substance induced in a dosage of 200 mg/kg a moderate but significant increase of the blood sugar level.

The "no-effect" dosage of the test substance by oral administration to rat is 50 mg/kg bw.