Glycerides, tallow sesqui-, hydrogenated, propoxylated

Endpoint summary

Description of key information

In a reliable repeated dose oral toxicity study in rats (Wistar, OECD TG 407), a structurally similar substance was adiministered via gavage to 5 rats/sex/dose at 0, 100, 300, 1000 mg/kg bw for 4 weeks. No death was observed in either sex. No clinical effects were observed in both sex of all dose groups.There was no effect observed upon haematological, clinical biochemistry or macroscopic examination at any dose that could be ascribed to the substance. Based on these results the NOAEL was considered to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Read-across to K1 study therefore K2 is the maximum Klimisch value.

Justification for type of information:

Read-across approach - see read-across justification in section 13.

Reason / purpose for cross-reference:

read-across source

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

- Amount of vehicle (if gavage): 5 ml/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The content of the test item was assumed to be nominally 100% for calculation. Before the start of the study formulations containing the test item in concentrations of 2 mg/mI and 200 mg/ml were analyzed to determine homogeneous distribution (not for the 2mg/ml formulation as it was a solution), content and stability of the test item in tap water. During the study homogeneity and content was checked twice.

Duration of treatment / exposure:

31 days

Frequency of treatment:

once daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

five

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
The dose levels used were based on the results of a pilot study. During this study Wistar rats (2 males and 2 females per dose group) received the test substance in doses of O, 65, 160, 400, 1000 mg/kg for a period of two weeks. No clinical findings or relevant effects on body weight development were observed in this study.

Positive control:

no positive control

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes (incl. Open Field Observations (OFO))
- Time schedule: day 8, 15, 22, 28

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: YES
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once, day 30
- How many animals: all dose groups incl. controls

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once, day 30
- How many animals: all dose groups incl. controls

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: FOB: once, day 25; MA: once, day 29
- Dose groups that were examined: all dose groups incl. controls
- Battery of functions tested: Functional Observational Battery (FOB); Motor Activity (MA)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (all dose groups and controls)

ORGAN Weights:
Adrenals, brain, epididymides, heart, kidneys, Liver, Ovaries, Spleen, Testes, Thymus, uterus

Fixed organs:
Adrenals, aorta, brain (cerebrum, cerebellum, ponslmedulla), epididymides, esophagus, eyes, eyelids, extraorbital lachrymal glands, femur, harderian glands, head (with nasal and paranasal cavities), heart, intestine (duodenum, jejunum, ileum, cecum, colon, rectum and remaining intestine), kidneys, larynx, liver, lymph nodes (mandibular, bronchial/hilus, and mesenteric), lung, mamma, optical nerves, ovaries, oviducts, pancreas, pharynx, pituitary, prostate, salivary glands, sciatic nerve, seminal vesicles (incl. coagulating glands), skeletal muscle (thigh), skin (mammary and muzzle), spinal cord (cervical, thoracic, lumbar), spleen, sternum, stomach (forestomach and glandular stomach), testes, thymus, thyroids (including parathyroid glands), tongue, trachea, ureter, urethra, urinary bladder, uterus with uterine cervix, vagina, Zymbal’s glands and all organs or tissues with macroscopic findings.

HISTOPATHOLOGY: Yes (high dose group and controls)
- Microscopic: Adrenals, brain (cerebrum, cerebellum, ponslmedulla), epididymides, femur, heart, intestine (duodenum, jejunum, ileum, cecum, colon, rectum and remaining intestine), kidneys, liver, lung, lymph nodes, ovaries, oviducts, pancreas, pituitary, prostate, salivary glands, sciatic nerve, seminal vesicles (incl. coagulating glands), skeletal muscle (thigh), skin (mammary and muzzle), spinal cord (cervical, thoracic, lumbar), spleen, sternum, stomach (forestomach and glandular stomach), testes, thymus, thyroids (including parathyroid glands), trachea, urinary bladder, uterus with uterine cervix, and all organs or tissues with macroscopic findings. Slides were prepared from the first five animals of all groups and evaluated from the control and the high concentration group.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Differential blood count was revealed that the number of leucocytes and lymphocytes was highest in the high dose males, but lowest in high dose females. These deviations were slight compared to the historical control values and the deviations were in opposite directions in males and females compared to control values. Given that there was no accopanying histopathology the study director concluded that these findings were of little toxicological significance.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Alanine aminotransferase activity in females at the top dose (1000 mg/kg bw/day) was significantly increased, but this difference was only silght compared to control values and there was no accompanying histopathology. The study director concluded that these findings were of little toxicological significance.

Plasma creatinine concentration was significantly decreased in males at the top dose and increased in females at the top dose. However, this difference was only silght compared to control values and there was no dose dependence in females. The deviations were in opposite directions in males and females compared to control values and given that there was no accopanying histopathology the study director concluded that these findings were of little toxicological significance.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

A slightly more pronounced hypertrophy of the follicular cell epithelium in the thyroid gland of the females at the top dose, both centrally located follicles and the perpheral follicles appeared hypertrophic. Hypertrophy was also observed in the animals from the other dose groups and in one animal from the contol group. However, this effect was considered to be indirect and adaptive by the study director.

Histopathological findings: neoplastic:

no effects observed

Details on results:

Haematology:

Differential blood count revealed as the only conspicuous finding, that the number of leucocytes and lymphocytes was highest in high dose males but was lowest in high dose females. However, these differences were slight compared to the differences between the means of historical control values and the upper 2 s-range in males and the lower 2s-range in females, respectively. Furthermore, the deviations from control value were in opposite directions in males and females and histopathological examinations revealed no corresponding findings. For these reasons a toxicological relevance was not inferred from these data.

Clinical chemistry:
Clinical aboratory tests revealed a significantly increased activity of alanine aminotransferase in females at 1000 mg/kg. However, the difference to control was relatively slight and histopathological examination of the liver produced no evidence for a treatment-related effect. Therefore, a toxicological relevance is not assumed. Determination of substrates showed the plasma creatinine concentration in males at 1000 mg/kg to be significantly decreased and in all treated female groups to be significantly increased. However, the differences to the respective control value were slight, no dose dependence was present in females, the deviation from the respective control group pointed in opposite directions in males and females and histopathological examination of kidneys produced no corresponding finding. On the basis of these results this was was not considered to be of toxicological relevance.

Histopathology:
The histopathological evaluation revealed a slightly more pronounced hypertrophy of the follicular cell epithelium in the thyroid gland of fernales ofthe high dose, in which not only centrally located follicles appeared hypertrophic but also follicles of the periphery. Hypertrophy was observed to a minimal degree also in females of the other dose groups including one control animal. Due to the slightly increased severity grade in females ofthe high dose group, an effect of the test substance cannot be completely ruled out. Such minimal changes are regarded to be caused by substances that interfere with general metabolic processes and are so far assessed as indirect and adaptive effects. If at all the findings in the present study were related to the treatment, they are therefore not considered as a primary adverse effect on thyroids. However, due to the missing dose response (incidence for follicular cell hypertrophy was: 1 /3/ 1 /3) and the lack of any other treatment-related changes a spontaneous occurrence e.g. by a general variability seems more likely.

Key result

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 adverse effects observed for any endpoint examined.

Key result

Critical effects observed:

no

Conclusions:

The NOAEL for the substance was 1000 mg/kg bw/day.

Executive summary:

In a repeated dose oral toxicity study in rats (Wistar, OECD TG 407), the substance was adiministered via gavage to 5 rats/sex/dose at 0, 100, 300, 1000 mg/kg bw for 4 weeks. No death was observed in either sex. No clinical effects were observed in both sex of all dose groups.There was no effect observed upon haematological, clinical biochemistry or macroscopic examination at any dose that could be ascribed to the substance. Based on these results the NOAEL was considered to be 1000 mg/kg bw/day. If at all the slight changes in thyroids of females at 1000 mg/kg were related to the treatment, they are regarded as an indirect and adaptive effect.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Sufficient to address requirements.

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