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EC number: 941-787-9 | CAS number: 98222-50-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- April 11, 2017 - June 6, 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- bis(2,4,4-trimethylpentan-2-yl)trisulfane
- EC Number:
- 941-787-9
- Cas Number:
- 98222-50-5
- Molecular formula:
- C16 H34 S3
- IUPAC Name:
- bis(2,4,4-trimethylpentan-2-yl)trisulfane
- Test material form:
- liquid
- Details on test material:
- Name: DAILUBE IS-30
Chemical Name: 1, 3-bis (2, 4, 4-trimethylpentan-2yl) trisulfane
Use: Lubricant Additive
Molecular Formula: CH3-C(CH3)2-CH2-C(CH3)2-SSS-C(CH3)2-CH2-C(CH3)2-CH3
Molecular Weight: 322 g/mol
Appearance Pale yellow
Physical State: Liquid
Batch Number: L002
Purity: 95.4% by weight
Storage: Room temperature, in the dark
Expiry Date: 2016/8/15
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The strain of rats employed in this study was chosen since it is widely used in general toxicity studies and reproductive/developmental toxicity studies, its characteristics are well known, and ample background data are available.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Atsugi Breeding Centre, Charles River Laboratories Japan, Inc.
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: 8 weeks
- Weight at study initiation: 422 to 488 g for males and 232 to 284 g for females
- Fasting period before study:
- Housing: plastic cages (W 440 × D 275 × H 180 mm: Hanyu-Seimitsu, Co., Ltd.) with bedding (ALPHA-dri, Shepherd Specialty Papers, Inc., Lot Nos. 11116 and 12216)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 20 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3
- Humidity (%): 50 ± 20%
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12 (lighting: 07:00 to 19:00)
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Dose volume was set at 5 mL/kg body weight and the dosing formulation was administered by gavage using a stomach tube.
Administered orally by gavage at 30, 100 or 320 mg/kg/day for 14 days before mating throughout the mating period until the day before necropsy (42 days in total) to males, for 14 days before mating and during the mating and gestation periods until day 13 of lactation (50 to 54 days in total) to females - Vehicle:
- other: 0.5% methylcellulose solution containing 0.1% tween 80
- Details on oral exposure:
- - PREPARATION OF DOSING SOLUTIONS:
For each dose concentration, the requisite amount of test article was weighed. An appropriate amount of vehicle was added, ultrasonic irradiation and stirring with a stirrer were carried out to suspend. Vehicle was added to make the specified volume and to prepare the 6, 20 and 64 mg/mL test suspensions (low, middle and high-dose formulations). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Three fractions (10mL each from the upper, middle and lower layers) were collected from each concentration and analyzed by HPLC method. In the results, the percentage to the nominal concentration ranged from 100.5 to 105.6 % and coefficient of variation (CV) ranged from 0.5 to 2.5%.
- Duration of treatment / exposure:
- 42 days for males (14 days prior to mating and 28 days after the start of mating),
50 to 54 days for females in the mating group (14 days prior to mating and throughout the mating and gestation periods until day 13 of lactation) and
42 days for females in the non-mated group. - Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 320 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes
Examinations
- Observations and examinations performed and frequency:
- 3 times a day
- Statistics:
- Bartlett’s test for homogeneity of variance; Homogeneous data were analyzed by Dunnett’s test; Heterogeneous data were analyzed by Steel test. Homogeneous data were analyzed by Student's t-test; Heterogeneous data were analyzed by Aspin-Welch's t-test;
The post-implantation loss index, delivery index, index of external abnormalities, livebirth index and viability index on PND 4 and 13 were analyzed by Wilcoxon’s rank-sum test;
The index of animals with abnormal estrous cycle, copulation index, insemination index,
fertility index, gestation index and sex ratio were calculated from the number of animals with abnormal estrous cycle, number of copulated animals, number of males that impregnated females, number of pregnant females and number of females that delivered liveborns, number of male or female pups which were counted for each group, and then analyzed by Fisher’s exact test;
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Administration Period:
There were no abnormalities in males and females during the administration period including the gestation and lactation periods.
Recovery Period:
No animals showed abnormalities
Grip Strength
Final Week of Administration Period
There were no effects of administration of test article on any test article administration group.
Final Week of Recovery Period
The males in the 320 mg/kg group showed a significantly low value in the forelimbs; however, it was judged to be an incidental significant difference since it was a mild change only in the forelimbs, there were no abnormalities in the final week of administration and there were no related changes in the detailed clinical observation.
Motor Activity
Final Week of Administration Period
There were no changes that are considered to be related to administration of the test article
Final Week of Recovery Period
No animals showed abnormalities - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Administration Period
In females of the mating group, at 320 mg/kg, significant low values were observed in the body weight on GDs 7, 14 and 20 and body weight gain during the gestation period, and a significant low value in body weight gain during the gestation period was observed at 100 mg/kg.
In the males and non-mated females group, there were no changes that are considered to be related to administration of the test article.
Females of the 30 mg/kg mating group showed a significantly low value in body weight on GD 20; however, no significant differences were observed in body weight gain during the gestation period and it was not a dose-dependent change and thus judged to be an incidental significant difference. A significant low value was observed in body weight on LD 4 in the 320 mg/kg group; however, it was judged to be an incidental significant difference as it is a transient slight change and body weight gain during the lactation period is not different from the control group.
Recovery Period
There were no significant differences between the 320 mg/kg group and the control group in males or females. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Administration Period
In females of the mating group, at 320 mg/kg, a significant low value or low trend were observed after GD 7, and the total food consumption during the gestation period was significantly low.
In males at 100 and 320 mg/kg and females of the non-mated group at 320 mg/kg, significant low values were observed on Day 2 of administration; however, it was judged to be a change without toxicological significance as it is a transient slight change and body weight during the pre-mating period is not different from the control group.
In females of the mating group, significant low values were observed on Day 2 of administration in the group of 30 mg/kg or more, and in the 100 and 320 mg/kg group, the total food consumption during the pre-mating period showed a significantly low value; however, it was judged to be a change without toxicological significance as it is a transient change and body weight during the pre-mating period is not different from the control group. Significant low values were observed on GD 7 at 30 and 100 mg/kg; however, it was judged to be a change without toxicological significance as it is a transient change and total food consumption during the gestation period is not different from the control group. There was no abnormality during the lactation period.
2) Recovery Period
There were no significant differences between the 320 mg/kg group and the control group in males. In females at 320 mg/kg, a significant high value was observed on day 2 of recovery, and the total food consumption during the recovery period showed a significant high value; however, it was judged to be a change without toxicological significance as body weight during the recovery period is not different from the control group. - Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no changes that are considered to be related to administration of the test article
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no changes that are considered to be related to administration of the test article
- Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Final Week of Administration Period
In males, small round epithelial cells (SREC) increased in urinary sediments in groups of 30 mg/kg and above.
No abnormalities were observed in other qualitative items in males and in qualitative items in females of the non-mated group, and no significant difference was observed in the urine volume between the control group and the test article administered group.
Final Week of Recovery Period
In males, small round epithelial cells (SREC) increased in urinary sediment in the 320 mg/kg group. However, there was a tendency to recover regard with the grade of change.
No abnormalities were observed in other qualitative items in males and qualitative items in females, and no significant difference was observed in the urine volume between the control group and the test article administered group. - Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the kidney, accumulation of α2µ globulin-derived hyaline droplets was observed in proximal renal tubular epithelial cells at 30 mg/kg or more in males, and regenerated renal tubules, granular cast and interstitial cell infiltration was observed with the increasing degree of this hyaline droplet. It is known that the accumulation of α2µ globulin is species-specifically expressed in male rats, which is enhanced by the administration of chemicals and further induces lesions characterized by renal tubular injury. From these facts, the lesions of the kidneys found in this study were considered not to be able to extrapolate to humans who don’t produce α2µ globulin, and were considered to have no toxicological significance. In addition, in males at 30 mg/kg or more, small round epithelial cells increased in the urinary sediment and kidney weight increased. However, both changes were thought to be secondary changes related to the histological findings of the kidney, and were considered to have no toxicological significance.
In the liver, hypertrophy of centrilobular hepatocytes was observed in males at 30 mg/kg or more, females of the mating group at 100 mg/kg or more, and females of the non-mated group at 320 mg/kg. Electron microscopy examination performed in some animals showed an increase of smooth endoplasmic reticulum in hepatocytes of the centrilobular zone. Therefore, the hypertrophy of hepatocytes is considered to be attributable to the induction of drug metabolizing enzymes as an adaptive response of the living body, and was considered to be of no toxicological significance. In addition, males at 320 mg/kg and females of the mating group at 100 mg/kg or more showed an increased liver weight. However, this increase regarded as secondary changes related to the histological findings of the liver was considered to have no toxicological significance.
At the end of recovery, accumulation of hyaline droplets in the proximal renal tubular epithelial cells of the kidney, granular cast, interstitial cell infiltration and the regenerated renal tubule showed recovery or a tendency to recover following the drug withdrawal. Therefore, all the changes in the kidneys due to accumulation of α2µ globulin are considered as reversible.
Recovery of hypertrophy of centrilobular hepatocytes in the liver is also suggests that it is a reversible change. In consideration of extrapolation to humans, it can be concluded that the toxicological effect on specific tissues was not induced up to 320 mg/kg, the maximum dose, in this study. - Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- effects observed, treatment-related
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 320 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 30 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
Applicant's summary and conclusion
- Conclusions:
- Based on these results, the repeated oral administrations of DAILUBE IS-30 under the conditions of this study caused suppressed body weight gain during the gestation period in females at 100 mg/kg or more. Therefore, it was judged that the no-observed-adverse-effect level (NOAEL) for the repeated dose toxicity of the test article was 320 mg/kg for males and 30 mg/kg for females.
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