Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: - | CAS number: -
- 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
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Test material form:
- other: semi-solid, wax-like (at 20°C)
- Details on test material:
- - Name of test material (as cited in study report): WS400102
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS: Wistar Crl:WI rats
- Source:Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Age at study initiation: 10 - 11 weeks
- Weight at study initiation: Males: 340 g – 395 g, Females: 230 g - 265 g
- Fasting period before study: overnight prior to treatment
- Housing: 5 animals of the same sex and group/cage with the exception of the mating and gestation/delivery period, when they
were paired or individually housed, respectively. (cage: Type II and/or III polycarbonate)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20,1-25
- Humidity (%): 36-70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 20, 60, 200 mg/ml
- Amount of vehicle (if gavage): 5 mL/kg bw
According to the results of a stability study, the test material was stable in Propylene glycol in concentration range of 20-200 mg/mL for 24 hours at room temperature (RT, 15-30ºC) and for up to three days when stored refrigerated at 2-8ºC (protected from light) and the homogeneity of the formulations was satisfactory. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of WS400102 formulations for concentration and homogeneity was performed using validated HPLC-UV method (CiToxLAB study code 11/350-316AN). The concentration analysis was performed on 3 occasions, during the first, fourth and last weeks of the treatment period. Recovery of WS400102 from propylene glycol was in the range from 97 to 105%.
- Duration of treatment / exposure:
- Main males: 35 days (14 days pre-mating, 14 days mating/post-mating period followed by an additional week)
Main females: ca. 47 days (14 days pre-mating, for up to 7 days mating period, through gestation til PPD 4)
Satellite females (nulliparous and nonpregnant): 35 days - Frequency of treatment:
- daily, 7 days/week
Doses / concentrationsopen allclose all
- 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:
- Main groups: 12 animals/sex/dose
Satellite group (20 female rats): 5 animals/dose
Offspring were not dosed. - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Based on available data and information from previous experimental work, including the results of a preliminary dose range finding study in the rat (7.5.1 Dose Range Finding Study 7 days rat_WS400102), the dose levels selected for the this study were 100, 300 and 1000 mg/kg bw/day. - Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- Observations and examinations performed and frequency
see Table 1a-c: Schedule and Dosing scheme ("Any other information on material and methods incl. tables")
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for signs of morbidity and mortality
- Time schedule: daily, general clinical observations
All animals were monitored for pertinent behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity including mortality.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least weekly
Observations in a standard arena: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern), or changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. self-mutilation, walking backwards); special attention were directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
BODY WEIGHT: Yes
- Time schedule: All adult Main and Satellite animals were weighed on Day 0, afterwards at least weekly and at termination.
Parent females were weighed on gestation Days GD 0, 7, 14 and 20 and on postpartal Days PPD0 (within 24 hours after parturition), and PPD5 (before termination).
FOOD CONSUMPTION: yes
-Time schedule: at least weekly
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy: Day 35
- Anaesthetic used for blood collection: Yes (pentobarbital)
- Animals fasted: Yes (overnight)
- How many animals: Subgroup A (5 main males/group), satellite females (5/group)
- Parameters examined: bloodcells, coagulation (APIT, PT).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy: Day 35
- Animals fasted: Yes (overnight)
- How many animals:Subgroup A (5 main males/group), satellite females (5/group)
- Parameters examined: Glucose, T-Bilirubin, Urea, Cholesterol, Creatinine, Phosphorus, Sodium, Potassium, Calcium, Chlorid, Total protein, Albumin, AST, ALT, ALKP, GGT, Bile acids.
URINALYSIS: Yes
- Time schedule for collection of urine: prior to necropsy
- Metabolism cages used for collection of urine: Yes (ca. 16 h)
- How many animals: Subgroup A (5 main males/group), satellite females (5/group)
- Parameters examined: Leukocytes, Nitrit, pH, protein, Glucose, Urobilinogen, Bilirubin, Ketones, Erythrocytes, Specific gravity, Sediment, Volume, Colour/Appearance.
NEUROBEHAVIOURAL EXAMINATION, Neurotoxicity: yes, FOB
- Time schedule: during the last exposure week (on Day 32)
- Dose groups that were examined: Main animals, 5 males/group, “subgroup A” and satellite females of all dose levels
- Battery of functions tested: sensory activity / grip strength / motor activity /general physical condition and behaviour of animals; a modified Irwin test was performed. - Sacrifice and pathology:
- Sacrifice and pathology
GROSS PATHOLOGY: Yes
- Animals: each adult animal, pups (PND4)
- Time schedule for the adults: on Day 35, i.e. one day after the last treatment following overnight period food deprivation, or PND5
HISTOPATHOLOGY: Yes, see Table 1-3 ("Any other information on materials and methods incl. tables") - Statistics:
- The statistical evaluation of appropriate data (marked † below) was performed with the statistical program package SPSS PC+4.0. The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant, Duncan Multiple Range test was used to access the significance of inter-group differences. Getting significant result at Bartlett’s test, the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test. Chi2 test was performed as feasible.
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:
- not examined
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In both sexes in the high dose group (1000mg/kg bw/day)
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In both sexes in the high dose group (1000mg/kg bw/day)
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In both sexes in the high dose group (1000mg/kg bw/day). Effects sharper in males.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Hepatic enlargement in high dose level groups
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Findings noted in the liver of males at 1000 mg/kg bw/day (High dose). Slightly effects in kidneys of females
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There was no mortality during the study. There were no clinical signs related to treatment.
BODY WEIGHT AND WEIGHT GAIN
There was no adverse effect of test item on body weight or body weight gain. Body weights were comparable to the control in all treated groups.
HAEMATOLOGY
Both males and females (satellite) at 1000 mg/kg (High dose) had decreased erythrocyte (RBC) count, haemoglobin concentration and haematocrit value. Compared to the control mean, the decrease was in the range of 8-10% in males and 10-12% in females. The differences were statistically significant. See Table 1 "Any other information on results incl. tables".
Females at 1000 mg/kg (High dose) had decreased leucocyte (WBC) counts. The difference attained statistical significance (p<0.01).
CLINICAL CHEMISTRY
Compared to the control mean, alkaline phosphatase activity (ALKP) was slightly elevated in males at 1000 mg/kg bw/day (High dose) and the mean value attained statistical significance.
Females at 1000 mg/kg bw/day (High dose) had elevated albumin (Alb.) concentration and consequently higher total protein (Tot.Prot) concentration and increased albumin to globulin (A/G) ration. The differences were statistically significant.
Increased calcium, sodium and chloride concentrations were measured in females at 1000 mg/kg bw/day.
See Table 2 "Any other information on results incl. tables".
URINALYSIS
There was no effect of treatment noted during urinalysis.
Urine sediment analysis showed similar results in all experimental groups including control.
NEUROBEHAVIOUR
There were no treatment related effects.There were no toxicologically significant changes in the animal behaviour, general physical condition, in the reactions to different type of stimuli in the control or treated groups.There was no effect of treatment noted during the assessment of foot splay or grip strength.
ORGAN WEIGHTS
Compared to controls, higher weights of liver were recorded for males at 1000 mg/kg bw/day (High dose). Liver of the High dose Satellite females were also slightly higher. The values for males were approximately 23-26% higher, than control and the differences attained statistical significance (p<0.01). In females, the increase was approximately of 16-19% and was statistically significant for body weight relative mean value.
See Table 3 and 4 "Any other information on results incl. tables".
GROSS PATHOLOGY
Test material-related macroscopic findings were observed in the liver at a dose level of 1000 mg/kg bw/day. The hepatic enlargement was recorded in 4 of 12 High Dose males.
Other occasional observations were considered to be incidental or within the physiological range.
HISTOPATHOLOGY: NON-NEOPLASTIC
Test material related microscopic findings were noted in the liver of males at 1000 mg/kg bw/day (High dose). Minimal to mild diffuse hepatocellular vacuolation of all lobes was seen in 6 of 9 males. Minimal to mild centrilobular hypertrophy was present in 4 of 9 High Dose males. The liver changes corresponded with organ weight changes and with macroscopic observations (enlargement).
In the Satellite females, minimal bilateral vacuolation and presence of cytoplasmic eosinophilic granules in the cortical tubules of kidneys were observed in 2/5 High dose animals.
See Table 5 "Any other information on results incl. tables".
Other changes were regarded as incidental.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 300 - <= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- haematology
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- System:
- other: slight changes in haematology, clinical chemistry, kidney (females only), liver (males only) in high dose animals
- Organ:
- kidney
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 1: Mean values of erythrocyte (RBC) count, haemoglobin concentration and haematocrit value in males and females
Groups/Dose (mg/kg/day) |
Control |
100 |
300 |
1000 |
|
|||
Males |
|
|||||||
RBC (M/uL) |
8.34 |
8.14 |
7.81* |
7.68* |
DN |
|||
Difference (%) |
-2 |
-6 |
-8 |
|
||||
Haemoglobin (g/dL) |
14.5 |
14.4 |
13.6* |
13.0** |
DN |
|||
Difference (%) |
-1 |
-6 |
-10 |
|
||||
Haematocrit (%) |
42.4 |
42.6 |
40.1* |
38.8** |
DN |
|||
Difference (%) |
0.5 |
-5 |
-8 |
|
||||
Females (satellite) |
|
|||||||
RBC (M/uL) |
7.81 |
7.54 |
7.48 |
7.02* |
DN |
|||
Difference (%) |
-3 |
-4 |
-10 |
|
||||
Haemoglobin (g/dL) |
15.3 |
14.9 |
14.7 |
13.5** |
DN |
|||
Difference (%) |
-3 |
-4 |
-12 |
|
||||
Haematocrit (%) |
43.2 |
41.5 |
41.3 |
38.1** |
DN |
|||
Difference (%) |
-4 |
-4 |
-12 |
|
* = p<0.05. ** = p<0.01 DN = Duncan's Multiple Range Test; % differences vs. control
Table 2: Mean values of selected clinical chemistry parameters in males and females
Groups/Dose (mg/kg/day) |
Control |
100 |
300 |
1000 |
|
|||
Males |
|
|||||||
ALKP (U/L) |
90.4 |
97.4 |
90.8 |
127.2** |
DN |
|||
Difference (%) |
8 |
0 |
41 |
|
||||
Females (satellite) |
|
|||||||
Albumin (g/L) |
35.9 |
37.0 |
39.0 |
42.9** |
DN |
|||
Difference (%) |
3 |
9 |
19 |
|
||||
Incidence |
1/5 |
3/5 |
5/5 |
|
||||
Total protein (g/L) |
63.8 |
65.0 |
66.6 |
71.4** |
DN |
|||
Difference (%) |
2 |
4 |
12 |
|
||||
A/G |
1.30 |
1.34 |
1.40 |
1.54** |
DN |
|||
Difference (%) |
3 |
8 |
18 |
|
||||
Calcium (mmol/L) |
2.52 |
2.58 |
2.64* |
2.70** |
DN |
|||
Difference (%) |
3 |
5 |
7 |
|
||||
Sodium (mmol/L) |
144.2 |
145.2 |
147.1* |
148.7** |
DN |
|||
Difference (%) |
1 |
2 |
3 |
|
||||
Chloride (mmol/L) |
99.9 |
101.1 |
102.5 |
104.6** |
DN |
|||
Difference (%) |
1 |
3 |
5 |
|
* = p<0.05. ** = p<0.01 DN = Duncan's Multiple Range Test;
% differences vs. control ,Incidence: incidence of elevated values
Table 3: Mean liver weights of males and satellite groups of females
/Dose (mg/kg/day) |
Control |
100 |
300 |
1000 |
|
|||
Males |
|
|||||||
Liver weight absolute (g) |
14.5 |
14.3 |
15.4 |
17.9** |
DN |
|||
Difference (%) |
- 2 |
6 |
23 |
|
||||
body weight relative (%) |
3.07 |
3.08 |
3.19 |
3.88** |
DN |
|||
Difference (%) |
0 |
4 |
26 |
|
||||
brain weight relative (%) |
663 |
651 |
705 |
822** |
DN |
|||
Difference (%) |
- 2 |
6 |
24 |
|
||||
Females (Satellite) |
|
|||||||
Liver weight absolute (g) |
7.5 |
7.5 |
8.5 |
8.7 |
NS |
|||
Difference (%) |
0 |
13 |
16 |
|
||||
body weight relative (%) |
2.81 |
2.85 |
3.04 |
3.35* |
DN |
|||
Difference (%) |
1 |
8 |
19 |
|
||||
brain weight relative (%) |
358 |
378 |
402 |
417 |
NS |
|||
Difference (%) |
6 |
12 |
16 |
|
*= p<0.05 ** = p<0.01 DN = Duncan's Multiple Range Test; NS = not significant
% differences vs. control
Table 4: Mean kidney weights of satellite females
Groups/Dose (mg/kg/day) |
Control |
100 |
300 |
1000 |
|
|||
Kidneys weight absolute (g) |
1.78 |
1.82 |
2.08 |
1.92 |
NS |
|||
Difference (%) |
3 |
17 |
8 |
|
||||
body weight relative (%) |
0.66 |
0.70 |
0.75* |
0.74* |
DN |
|||
Difference (%) |
5 |
13 |
11 |
|
||||
brain weight relative (%) |
85 |
92 |
99 |
92 |
NS |
|||
Difference (%) |
9 |
17 |
9 |
|
*= p<0.05. DN = Duncan's Multiple Range Test; NS = not significant , % differences vs. control
Table 5: Incidence of the liver lesions in males
Groups/Dose (mg/kg/day) |
Control |
100 |
300 |
1000 |
||
No. of examined |
5 |
0 |
0 |
9 |
||
Without alteration |
5/5 |
- |
- |
3/9 |
||
Vacuolation: total |
0/5 |
- |
- |
6/9 |
||
minimal |
0 |
- |
- |
2 |
||
mild |
0 |
- |
- |
4 |
||
Hypertrophy: total |
0/5 |
- |
- |
4/9 |
||
minimal |
0 |
- |
- |
2 |
||
mild |
0 |
- |
- |
2 |
Applicant's summary and conclusion
- Conclusions:
- For the repeated dose toxicity endpoint the NOAEL of WS400102 administered at oral route to Wistar rats for 35 consecutive days is considered to be the mid-dose level of 300 mg/kg bw/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Although ECHA is providing a lot of online material in your language, part of this page is only in English. More about ECHA’s multilingual practice.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
the-echa-website-uses-cookies
find-out-more-on how-we-use-cookies