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Administrative data

Description of key information

A 13 weeks repeated dose toxicity on an analogue substance polyoxyethylene (1-6) alkylamine (C12-C22) fatty acid (C12-C22) ester is used as read-across information. The substance was added to the feed at a concentration of 0.03% , 0.1% , 0.3% and 1%. Mice and rats were fed this diet for 3 months. According to the results a max. Safety level (NOEL) in mice and rats after the administration of samples was assumed to be 0.1%. Values of 104.0 mg/kg/day for the male and 116.2 mg/kg/day for the female rats will be obtained from their average food consumption. For the mice, the values will be 104.8 mg/kg/day for the males and 132.7% mg/kg/day for the females as their average food consumption is 4 g/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Remarks:
other: 13 weeks
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study design appears to follow OECD guideline without detailed documentation.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
No information on purity of the test substance, temperature, humidity, and light condition; Homogeneity, concentration, stability of the test substance in the application media not analyzed; Several observations/parameters were not performed/measured.
GLP compliance:
no
Remarks:
Study pre-dates GLP requirements.
Limit test:
no
Species:
other: mice and rats
Strain:
other: Mice: ICR; Rats: SD-JCL
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: feed
Details on oral exposure:
Concentration in feed were 0% (vehicle), 0.03% , 0.1% , 0.3% and 1%.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
104.0 mg/kg/day for male and 116.2 mg/kg/day for female rats obtained from average food consumption represent the dose of 0.1% added group.
104.8 mg/kg/day for male and 132.7 mg/kg/day for female mice obtained from average food consumption represent the dose of 0.1% added group.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
No. of animals per sex per dose:
10 per sex per dose
Observations and examinations performed and frequency:
Body weights and food intakes were measured once a week. However, it was difficult to measure the food intake so that measurement was omitted.
The general conditions were observed when bodyweights were measured and optionally for some other items.
Urinalysis was conducted when administration ended after 13 weeks. For fresh urine, glucose, protein, occult blood, pH and urobilinogen were measured.
Hematological tests and hematological biochemical tests were performed at the end of administration after 13 weeks.
Sacrifice and pathology:
Autopsies were performed on animals after withdrawal of blodd samples. Pathohistological examinations were carried out for major organs.
Statistics:
t-test
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
1) Body Weight Gains
Body weight gains for the test mice at 1% level were significantly lower than those for the controls. In rats, body weight gains for the males at 0.3% and 1% levels and for the females at 1% level showed a significant decrease compared to those for the controls.
2) Food Consumption
Food consumption values for the male and female rats at 1% level were significantly lower than those for the other test rats at the beginning of the tests. Food was given freely to the test animals as accurate weighting of the food consumed was very difficult.
3) Haematology
Red cell counts and Hb values for the test mice and rats showed a dose-related decrease. This trend was remarkable for the male rats at 0.3% and 1% levels and for the female rats at 1% level.
4) Blood biochemistry
Total protein values for the male at 0.3% and 1% levels and for the female rats at 1% level showed a significant decrease. Urea-N values showed a dose-related increase. For the male and female rats at 1% level the values were significantly higher than those for the controls. No other abnormalities were found in the test animals.
5) Organ weights
Examination of the relative organ weights for the testing animals revealed the liver weights for the mice at 1% level, the liver weights and the spleen weights for the rats of both sexes at 1% level to be significantly higher than those for the controls.
6) Patho-histological findings
The white pulp of the spleen of the mice of both sexes at 0.3% and 1% levels were found to be in proliferation and growth of the ovarian follicles of the female mice at 1% level insufficient. For the male rats at 1% level, atrophy in the glomerulus, degenerated epithelial cells of the seminiferous tubule of the seminal glands, and abnormal spermatogenesis were found.
Dose descriptor:
NOEL
Effect level:
ca. 104 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on no abnormalities should occur.
Dose descriptor:
NOEL
Effect level:
ca. 116.2 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on no abnormalities should occur.
Critical effects observed:
not specified
Conclusions:
The max. level of the substance at which no abnormalities should occur is in between 0.1% and 0.3%. Consequently, if 0.1% is determined as the max. Safety level of the substance, values of 104.0 mg/kg/day for the male and 116.2 mg/kg/day for the female rats will be obtained from their average food consumption. For the mice, the values will be 104.8 mg/kg/day for the males and 132.7 mg/kg/day for the females as their average food consumption is 4 g/day.
Executive summary:

Polyoxyethlene (1-6) alkylamine (C12-C22) fatty acid (C12-C22) ester was added to the feed at a concentration of 0.03% , 0.1% , 0.3% and 1%. Mice and rats were fed this diet for 3 months. The results showed body weight gains for the test mice at 1% level were significantly lower than those for the controls. In rats, body weight gains for the males at 0.3% and 1% levels and for the females at 1% level showed a significant decrease compared to those for the controls.

Food consumption values for the male and female rats at 1% level were significantly lower than those for the other test rats at the beginning of the tests.

As hematological finding, red cell counts and Hb values for the test mice and rats showed a dose-related decrease. This trend was remarkable for the male rats at 0.3% and 1% levels and for the female rats at 1% level.

As hematological biochemical findings, total protein values for the male at 0.3% and 1% levels and for the female rats at 1% level showed a significant decrease. Urea-N values showed a dose-related increase. For the male and female rats at 1% level the values were significantly higher than those for the controls. No other abnormalities were found in the test animals.

Regarding organ weights, the liver weights for the mice at 1% level, the liver weights and the spleen weights for the rats of both sexes at 1% level were found to be significantly higher than those for the controls.

Regarding pathohistological findings, the white pulp of the spleen of the mice of both sexes at 0.3% and 1% levels were found to be in proliferation and growth of the ovarian follicles of the female mice at 1% level insufficient. For the male rats at 1% level, atrophy in the glomerulus, degenerated epithelial cells of the seminiferous tubule of the seminal glands, and abnormal spermatogenesis were found.

The max. level of the substance at which no abnormalities should occur is in between 0.1% and 0.3%. Consequently, if 0.1% is determined as the max. Safety level of the substance, values of 104.0 mg/kg/day for the male and 116.2 mg/kg/day for the female rats will be obtained from their average food consumption. For the mice, the values will be 104.8 mg/kg/day for the males and 132.7 mg/kg/day for the females as their average food consumption is 4 g/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
104 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Read across approach from structural analogue.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Two repeated dose toxicity studies were available as read-across information based on structural analogues. Study carried out on polyoxyethylene (1-6) alkylamine (C12-C22) fatty acid (C12-C22) ester is selected as the key information and as the basis for classification. The other study tested on polyoxyethylene stearylamine stearate, however is regarded as supporting information since it comes from the same laboratories and with comparable reliability. The deficit of the later study is that it did not verify/estimate the actual dose as the testing substance that received by the testing animals. Both 90 days toxicity study have drawn the similar conclusion that the NOEL level is approximate 0.1 as concentration in the feed, representing values of 104.0 mg/kg/day for the male and 116.2 mg/kg/day for the female rats, and 104.8 mg/kg/day for the male and 132.7 mg/kg/day for the female mice respectively according to their average food consumption.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No primary data on notified substance. The information is from structural analogue.

Justification for classification or non-classification

No primary data is available on the notified substance. Key data comes from a 90 days study on structural analogue "polyoxyethylene (1-6) alkylamine (C12-C22) fatty acid (C12-C22) ester". The majority of components (about 80% w/w) of substance

"Reaction product of: stearyl-diethanol-amine with C16 -18 saturated fatty acids" represents a subgroup (which has fatty acids chain length C16 - C18) of the tested substance (which has fatty acids chain length from C12 to C22), therefore substances are structurally very similar and the two mechanisms of action are comparable. Thus the read-across approach is considered to be absolutely reliable. Based on read-across information the substance does not need to be classified as the NOEL value established in key study is 104.0 mg/kg/day for the male and 116.2 mg/kg/day for the female rats, and 104.8 mg/kg/day for the male and 132.7 mg/kg/day for the female mice respectively according to their average food consumption.