Propylidynetrimethanol, ethoxylated

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline GLP study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Propylidynetrimethanol, ethoxylated

EC Number:

500-110-3

EC Name:

Propylidynetrimethanol, ethoxylated

Cas Number:

50586-59-9

Molecular formula:

C3H5(CH2O(C2H4O)nH) sum of n: >1 - <6.5 mol EO

IUPAC Name:

Propylidynetrimethanol, ethoxylated

Details on test material:

- Name of test material (as cited in study report): Lupranol VP 9236
- Purity: 99.9 g/100 g
- Physical state: liquid (viscous)/colorless, clearThe analysis demonstrated the stability of the test substance in the vehicle (drinking water) up to 4 hours at room temperature. In conclusion the test substance preparations were made daily prior to the administration and therefore the stability was verified.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

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:

For the present study no appropriate analytical method was found to monitor the stability of Lupranol VP 9236 in drinking water. Therefore further analyses were necessary after the finalization of the report. An additionally stability analysis was carried out at the low dose level administered in
this 28 day repeated toxicity study (1g/100 ml). This analysis demonstrated the stability of the test substance in the vehicle (drinking water) up to 4 hours at room temperature. In conclusion the test substance preparations were made daily prior to the administration and therefore the stability was verified.

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 300 and 1000 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

five

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection : By request of the sponsor

Positive control:

no positive control

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes (incl. Open Field Observations (OFO))
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: YES
- Time schedule for examinations: weekly

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: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once, day 29
- How many animals: all dose groups incl. controls

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once, day 29
- How many animals: all dose groups incl. controls

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: FOB: once, day 26; MA: once, day 27
- 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, Thyriod glands

Fixed organs:
All gross lesions; Salivary glands (mandibular and sublingual glands); Esophagus; Stomach (forestomach and glandular stomach); Duodenum, jejunum and ileum; Cecum, colon and rectum; Liver; Pancreas; Brain; Pituitary gland; Sciatic nerve; Spinal cord (cervical, thoracic and lumbar cords); Eyes; Adrenal glands; Thyroid glands; Parathyroid glands; Trachea; Lungs; Pharynx; Larynx; Nose (nasal cavity); Aorta; Heart; Bone marrow (femur); Lymph nodes (mesenteric and axillary lymph nodes); Spleen; Thymus; Kidneys; Urinary bladder; Testes; Ovaries; Oviducts, uterus and vagina; Epididymides, prostate and seminal vesicle;. Female mammary gland; Skin; Skeletal muscle; Sternum with marrow; Femur with knee joint; Extraorbital lacrimal glands

HISTOPATHOLOGY: Yes (high dose group and controls)
- Microscopic:
The hematoxylin-eosin stained slides of the following organs were assessed by light-microscopy for the control and high dose group animals.
all gross lesions, Adrenal glands; Aorta; Bone marrow (femur); Brain; Cecum, colon and rectum; Duodenum (with Peyer’s patches); Esophagus; Eyes with optic nerve; Female mammary gland; Heart; Kidneys; Liver; Lungs; Lymph nodes (mesenteric and axillary lymph nodes); Ovaries; Oviducts, uterus and vagina; Pancreas; Parathyroid glands; Pituitary gland; Prostate, seminal vesicle and epididymides; Salivary glands mandibular and sublingual glands); Sciatic nerve; Skin; Spinal cord (cervical, thoracic and lumbar cords); Spleen; Stomach (forestomach and glandular stomach); Testes; Thymus; Thyroid glands; Trachea; Urinary bladder.
Organs embedded in paraplast for the low and mid dose animals of the following organs: For all gross lesions and the liver

Results and discussion

Results of examinations

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

Food efficiency:

no effects observed

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

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:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

OPHTHALMOSCOPIC EXAMINATION:
The observed corneal stipplings and remainders of the papillary membrane were equally distributed between the dosed animals and the controls as well as were without any doseresponse relationship. Therefore, these findings were clearly not related to treatment and without any toxicological relevance.

HAEMATOLOGY
Concerning hematology parameter values no treatment-related, adverse effects were measured. In the male rats of the 1000 mg/kg bw/d dose group the platelet counts were decreased compared to the controls. This change was the only one concerning hematology and hemostaseology parameters. Additionally, the median of the platelet counts was within the historical control range (724 – 999 G/L). Therefore, this deviation was regarded as incidental and not adverse.

CLINICAL CHEMISTRY
In the male rats of the 300 and 1000 mg/kg bw/d dose groups the cholesterol levels were increased compared to the controls. This increase was dose-dependent and slightly above the historical control range (1.45 – 1.89 mmol/L). However, this was the only parameter in clinical chemistry which was deviated in these animals and therefore it is regarded as nonadverse, although it cannot be excluded that this change was treatment-related.

NEUROBEHAVIOUR
Motor Activity: Regarding the overall motor activity, no substance-related findings were observed. Comparing the single intervals with the control groups, motor activity was significantly increased in males of group 3 and group 1 at interval 11. This single occurrence was without any significant influence on the overall motor activity and therefore assessed as not toxicologically relevant.
FOB: Deviations from "zero values" were obtained in several animals. However, as most findings were equally distributed between treated groups and controls, were without a doseresponse relationship or occurred in single animals only, these observations were considered to have been incidental.

ORGAN WEIGHTS
Absolute Weights: Compared to controls (= 100%) only the kidney weights of 100 mg/kg (89%, p<0.05) and 300 mg/kg (89%, p<0.05) dose group females revealed a statistical significant weight decrease and the thymus of 100 mg/kg (121%, p<0.05) females showed a statistically significant weight increase. These variations are considered incidental and not related to treatment due to missing dose-response relationship.
All other mean absolute weight parameters did not show relevant differences compared to the control group.
Relative Weights: Compared to controls (= 100%) only the thymus weights of 100 mg/kg (122%, p<0.05) dose group females revealed a statistical significant weight increase. This variation is considered incidental and not related to treatment due to missing dose-response relationship.
All other mean relative weight parameters did not show relevant differences compared to the control group.

Effect levels

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

other: Regarding clinical examinations, clinical pathology as well as pathology the limit dose of 1000 mg/kg bw did not cause any signs of toxicity

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

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

Executive summary:

In a repeated dose oral toxicity study in rats (Wistar, OECD TG 407), the test substance was administered via gavage to 5 rats/sex/dose at 0, 100, 300, 1000 mg/kg bw for 4 weeks. Regarding clinical examination, clinical pathology, the oral administration by gavage up to and including the limit dose of 1000 mg/kg bw and day over a period of 4 weeks did not cause any signs of toxicity. Based on these results the NOAEL was considered to be 1000 mg/kg bw/day in both sexes.