Dioctadecyl 3,3'-thiodipropionate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2022

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

June 2018

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Dioctadecyl 3,3'-thiodipropionate

EC Number:

211-750-5

EC Name:

Dioctadecyl 3,3'-thiodipropionate

Cas Number:

693-36-7

Molecular formula:

C42H82O4S

IUPAC Name:

dioctadecyl 3,3'-thiodipropionate

Test material form:

solid: flakes

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI(Han)

Details on species / strain selection:

Rats are a generally accepted species for the type of study and for the specific strain, extensive experience and historical control data is available at the laboratory.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: at least 5-6 weeks
- Housing: Up to 5 animals of the same sex and same dosing group together. Polycarbonate cages (Makrolon type IV, height 18 cm or Makrolon type 2000P, height 21.5 cm) containing sterilized wooden fibers as bedding material (Safe S 8 15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. During locomotor activity monitoring, animals are housed individually in a Hi-temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20.3 cm) without cage-enrichment, bedding material, food and water.
- Diet (e.g. ad libitum): SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany ad libitum. During motor activity measurements, animals will not have access to food for a maximum of 2 hours.
- Water (e.g. ad libitum): Municipal tap water ad libitum
- Acclimation period: ca. 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 17.08.2022 - 30.11.2022

Administration / exposure

Route of administration:

oral: gavage

Details on route of administration:

Gavage is a preferred administration method for the study conducted and was found to be well tolerated in preliminary studies.

Vehicle:

methylcellulose

Remarks:

1% Methylcellulose

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The dosing formulations will be prepared at least weekly, filled out in daily portions and stored in the refrigerator protected from light. Dosing formulations will be removed from the refrigerator at least 30 minutes before dosing and will be stirred at room temperature.
No adjustment will be made for specific gravity of the test item and vehicle. No correction will be made for the purity/composition of the test item or vehicle.

VEHICLE
- Justification for use and choice of vehicle (if other than water): the test item is not soluble in water, 1% MC resulted in homogenous and stable dispersions which were well tolerated by the animals in a preliminary study.
- Concentration in vehicle: 0, 10, 30, 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration and homogeneity analysis.
Stability analyses performed previously in conjunction with the method development and validation demonstrated that the test material is stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in the present study.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses were selected based on the results of a previous dose-range finding study. The highest dose selected represents the limit dose for the study design. Dose spacing was conducted with a factor of ca. 3 in accordance with the OECD guideline.
- Fasting period before blood sampling for clinical biochemistry: yes (overnight)
- Dose range finding studies: a 14-day dose range findings study was previously conducted.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality check at least twice daily beginning upon arrival through termination/release. Cageside observations at least once daily; from Day 1 at 0 to 1 hours postdose.
Except on days of receipt and necropsy where frequency will be at least once daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first administration of the test material and weekly during the Treatment Period.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly; from at least Day 1 and throughout the study.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water consumption is monitored on a regular basis by visual inspection of the water bottles.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pre-treatment period (all main study animals); week 13 (control and high dose group, if treatment-related findings are noted, the other animals will also be examined.)

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of treatment
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: White Blood Cell (WBC), Neutrophils (absolute), Lymphocytes (absolute), Monocytes (absolute), Eosinophils (absolute), Basophils (absolute), Large unstained cells (LUC) (absolute), Red Blood Cell (RBC), Reticulocytes (absolute), Red Blood Cell Distribution Width (RDW), Hemoglobin, Hematocrit, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), Platelets; Coagulation: Prothrombin time (PT), Activated partial thromboplastin time (APTT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of treatment
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: see table below.

PLASMA/SERUM HORMONES/LIPIDS: Yes
Time schedule for collection of blood: end of treatment
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: see table below (clinical chemistry)

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Once during the Dosing Period. The first 5 animals per sex per group during Week 13.
- Battery of functions tested: see table below. Locomotor activity (1h recording period under normal laboratory light conditions, using a computerized monitoring system).

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; complete necropsy examination, which will include evaluation of the carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues.
Organ weights: see table below

HISTOPATHOLOGY: Yes (see table)

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Target system / organ toxicity

Critical effects observed:

not specified