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EC number: 288-307-8 | CAS number: 85711-47-3
- 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
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- 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:
- other: Well documented and reported study fully adequate for assessment. The study was conducted according to an internationally accepted technical guideline and in compliance with GLP in a recognized contract research organization.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- of 1996
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Sprague Dawley rats, strain: Crl:CD(SD) with appropriate range of bodyweight at study start.
- Source: Charles River (UK) Ltd.
- Age at treatment start: 72 days.
- Weight at treatment start: Males: minimum 337 g, maximum 417 g,
Females: minimum 227 g, maximum 293 g.
- Housing Inside a barriered rodent facility:
all animals pre-pairing + toxicity subgroups: In groups up to 5 by sex in solid floor polycarbonate cages.
during pairing (1 male+1 female/cage): In RB3 modified polycarbonate cages with stainless steel grid-floor over absorbent paper-lined trays.
males after pairing: In groups up to 5 in solid floor polycarbonate cages.
females during gestation and lactation: Females housed individually (+litter) in solid floor polycarbonate cages.
- Bedding material (in solid floor cages): Wood based bedding, sterilised by autoclaving before use.
- Cage enrichment: Aspen chew block + plastic shelter (except during pairing or post Gestation Day 20).
- Diet (ad libitum): Standard rodent diet (SDS VRF1 Certified) without antibiotic, chemotherapeutic or prophylactic agent.
- Fasting (diet withheld): Main phase males and Toxicity phase females overnight before blood sampling for clinical pathology.
- Water (ad libitum): Potable drinking water from the public supply.
- Acclimation period: 7 days before treatment start, under laboratory conditions.
Routine analysis of the batch of diet used and water, chew blocks and bedding material did not provide evidence of contamination that might have prejudiced the study.
IN-LIFE DATES:
- Duration of test, males & toxicity phase females: Five weeks
Duration of test, main phase females (i.e. reproductive subgroup): From 14 days prior to pairing to day 7 of lactation.
Duration of test, offspring: From birth to day 7 of lactation.
ENVIRONMENTAL CONDITIONS
Air conditioned room kept at positve pressure without re-circulation of the filtered fresh air supplied to the room.
Controlled environment, environmental conditions were set at:
- Temperature (°C): 21 ± 2°C
- Relative Humidity (%): 40 to 70%
- Photoperiod (artificial lighting): 12 hrs day / 12 hrs night
- Rate of air exchange: At least 15 changes/h
Deviations from the target ranges for temperature and relative humidity were not evident. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- - Concentration in vehicle: The concentration of the test material in vehicle varied between dose groups thus allowing constant dosage volume in terms of mL/kg bw/day.
- Amount (dose volume by gavage): 5 mL/kg bw/day.
Actual dose volumes were calculated at about weekly or shorter intervals accounting for the latest bodyweight. Litter animals were not dosed.
- For concentrations of test material in vehicle at different dose levels, see Table 1 in "Any other information on materials and methods incl. tables"
- Justification for choice of vehicle:
The suitability of corn oil as a vehicle was established during the 14-day range-finding study:
Endpoint study record "7.5.1 Repeated dose toxicity: oral - 14d_range-finding_gavage_HLS_GAH0175".
In addition, in the present main study, concentrations of dose formulations were chemically analysed. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Chemical analysis of test material formulations by high performance liquid chromatography coupled with a mass spectrometer (HPLC-MS/MS).
- Mean concentrations of the test material formulations (verified for first and 7th treatment week) were confirmed at each dose level.
Chemical analysis confirmed that the mean concentrations of WS400107 in prepared formulations were within 93% to 100% of the corresponding
nominal concentration, thus confirming acceptable accuracy of formulation for dosing of the animals.
- Homogeneity and stability of test material formulations at 2 and 200 mg/L and at storage and handling conditions similar to those adopted for dosing of the animals were confirmed. - Duration of treatment / exposure:
- - Treatment period, males & toxicity phase females: Daily, for five consecutive weeks, in males commencing 14 days prior to pairing
- Treatment period, main phase females (i.e. reproductive subgroup): 44 to 51 days (from 14 days prior to pairing to Day 6 of lactation)
- Offspring were not dosed - Frequency of treatment:
- Daily, 7 days/week (during parturition, dosing omitted as appropriate)
- Remarks:
- Doses / Concentrations:
0 (vehicle control), 150, 400, 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- Toxicity phase animals: */ 5 females
Main phase animals (i.e. reproductive subgroups): 10 males / 10 females
*Explanatory note by the notifier:
Examinations assigned to the toxicity phase females to meet the requirements of a 28-day repeat dose oral toxicity study were also assigned to 5 (for some examinations to 10) main phase males per dose group. Therefore, these 5 main phase males per dose group are called also "toxicity subgroup" in the present robust study summary for clarification. After pairing with main phase females, all males (F0) were killed at the same time (Week 6). - Control animals:
- yes, concurrent vehicle
- Details on study design:
- This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study
(OECD 422 test guideline). Therefore, animals initially entering the study were divided into toxicity subgroup animals (toxicity phase) and reproductive subgroup animals (main phase), whereby 5 of the 10 F0 males (used for pairing) per dose group formed the toxicity male subgroups.
Dose selection was based on the results of a 14-day preliminary oral (gavage) toxicity study in the rat in which dose levels of 100, 300 or 1000 mg/kg/day did not have any severe toxic effects on young adult animals (females nulliparous and non-pregnant) preventing the choice of up to 1000 mg/kg/day in the present OECD 422 toxicity study. - Positive control:
- Not included in the study.
- Observations and examinations performed and frequency:
- Clinical observations performed and frequency:
- Clinical signs : At least twice a day
- Detailed physical examination
and arena observations: Before treatment start and at least once a treatment week (except possibly 1 female taking 5 to 8 days for pairing).
- Functional Observation Battery:* During treatment week 5 (before dosing) on all toxicity subgroup animals (5 males + 5 females/group).
- Body weight, all males: About weekly throughout the study.
Body weight, Toxicity Females: About weekly throughout the study.
Body weight, Repro. Females: Weekly for pre-pairing period; on gestation days 0, 6, 13, 20; on lactation days 1, 4 & 7.
- Food consumption, all males: Weekly for pre-pairing period and for the period after mating.
Food cons., Toxicity Females: About weekly throughout the study.
Food cons., Repro. Females: Weekly for pre-pairing period, during gestation for days 0-6, 6-13, 13-20, during lactation for days 1-4 & 4-7.
* FOB including sensory reactivity tests (approach, touch, auditory startle reflex, tail pinching), grip strength and motor activity.
Haematological examinations (only for toxicity subgroup animals) during treatment week 5 after functional observation battery:
Red blood cell count, reticulocyte count, white blood cell count, platelet count, hemoglobin concentration, hematocrit value, differential leukocyte counts,
protrombin time, activated partial thromboplastin time, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration.
Blood (plasma) chemical examinations (only for toxicity subgroup animals) during treatment week 5 after functional observation battery:
Total protein, albumin, A/G ratio, urea, creatinine, glucose, total cholesterol, triglycerides, total bilirubin, bile acids, sodium, potassium, chloride,
calcium, inorganic phosphorus, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase.
This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study
(OECD 422 test guideline). Therefore, some of the examinations were confined to toxicity subgroup animals, as indicated above. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, see below
WEIGHING OF ORGANS: Yes, see below
HISTOPATHOLOGY: Yes, see below
Terminal sacrifice
- all males (F0) and toxicity subgr. females: Killed in Week 6, after completion of the Treatment Week 5 investigations.
- reproductive subgr. females & offspring: Killed on Day 7 post partum.
(1 high dose female was killed after mating in poor clinical condition. It was confirmed to be non-pregnant)
(1 control female failed to mate and therefore was killed in Week 8 following 7 weeks of treatment)
Gross pathology:
- adult/parental animals: Full macroscopic examination.
- offspring, Lactation Day 7: Careful external macroscopic examination of all survivors for gross abnormalities.
- externally abnormal offspring
and premature deaths: Internal macroscopic examination including assessment of the presence of milk in the stomach, where possible. (Missing or grossly autolysed or cannibalised offspring could not be examined).
Organs Weights:
- all males (F0) +
toxicity subgroup females: Adrenals, brain, epididymides, heart, kidneys, liver, ovaries, prostate, seminal vesicles with coagulation gland,
spleen, testes, thymus, uterus with cervix & oviducts.
- dams: Ovaries
Histopathology:
- toxicity subgroups: The following organs were microscopically observed for the control and 1000 mg/kg bw/day toxicity subgroups:
Brain, eyes, pituitary gland, thyroid with parathyroids, heart, thymus, liver, spleen, adrenals, kidneys, testes,
epididymides, ovaries, lung, trachea, oesophagus, stomach, duodenum, jejunum, ileum, caecum, rectum, colon,
Peyer's patch, lymph node (axillary, mesenteric), urinary bladder, uterus (with cervix & oviducts), vagina,
spinal cord, sciatic nerve, skeletal muscle, sternum with marrow, seminal vesicle & coagulation gland, prostate.
In addition, the duodenum, jejunum, ileum, mesenteric lymph nodes, seminal vesicles and prostate
were also examined by light microscopy for the remaining F0 males of the control and 1000 mg/kg bw/day
groups and all adult males and toxicity subgroup females of the 150 and 400 mg/kg bw/day groups and any
gross lesions for all adult animals.
- reproductive subgroups All above organs/tissues from a premature death (1 high dose female). Gross lesions from adult dams comprised only focal hairloss not necessating any examination by light microscopy. - Other examinations:
- Reproductive and developmental toxicity parameters (addressed in separate endpoints).
- Statistics:
- Statistical analysis of grip strength, motor activity, bodyweight, food consumption, organ weight, litter size, survival indices & clinical pathology data:
- Parametric analysis, if Bartlett's test for variance homogeneity was not significant at the 1% level.
F1 approximate test for monotonicity of dose-response. If this F1 test was not significant at the 1% level, Williams' test for a monotonic trend was applied.
If this F1 test was significant, suggesting that the dose-response was not monotone , the Dunnett's test was performed instead.
- Non-parametric analysis, if Bartlett's test was still significant at the 1% level following logarithmic and square-root transformations.
H1 approximate test for monotonicity of dose-response. If this H1 test was not significant at the 1% level, Shirley's test for a monotonic trend was applied.
If this H1 test significant, i.e. dose-response not monotone, then Steel's test instead.
Grip strength, motor activity, survival indices and clinical pathology data
if 75% of the data (across all groups) were the same value, pairwise comparison of each dose group against the control by Fisher’s Exact tests.
Organ weight data
Covariance analysis using terminal bodyweight as covariate (Angervall & Carlstrom, 1963)
Gestation length
Exact (or asymptotic) two-tailed Linear-by-linear test (Cytel 1995), with equally spaced scores.*
Oestrous cycles
Exact (or asymptotic) 1-tailed (upper tail) Linear-by-linear test (Cytel 1995)*
* If significant (p<0.05), exclusion of the highest dose group and re-testing until no longer significant (p≥0.05).
For statistical references, see next field. - Clinical signs:
- no effects observed
- Description (incidence and severity):
- attributable to treatment with the test material
- Mortality:
- no mortality observed
- Description (incidence):
- attributable to treatment with the test material
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- but not considered to represent adverse effects
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- but not considered to represent adverse effects
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- but toxicological significance is unclear
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- but not representing toxicity or toxicological significance unclear
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- but not representing toxicity or toxicological significance unclear
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS, NEUROBEHAVIOUR AND MORTALITY
Mortality, clinical signs or effects on sensory reactivity, grip strength or motor activity attributable to treatment with the test material were not evident. One high dose female of the reproductive subgroup was killed during the gestation phase, because of its poor clinical condition (thin built, hunched posture, piloerection, ungroomed fur and 13 g bodyweight loss over 14 days, confirmed to be not pregnant at necropsy). One control female of the reproductive subgroup failed to mate and therefore was killed after 7 weeks of treatment (Week 8).
BODYWEIGHT GAIN AND FOOD CONSUMPTION
A dose related adverse effect on bodyweight gain was evident in males over the 5 weeks of treatment attaining statistical significance at 400 and 1000 mg/kg bw/day. Nulliparous females were unaffected by treatment, but in dams treated with 1000 mg/kg bw/day bodyweight gain was statistically significantly lower than in concurrent controls during gestation Days 6 to 13 and overall during gestation Days 0 to 20. Food consumption was lower than in concurrent controls in males at 1000 mg/kg/day during the 5-week treatment period and in dams at 1000 mg/kg/day on lactation Days 4 to 7.
CLINICAL PATHOLOGY
Changes in haematology or clinical chemistry (blood plasma) parameters were not considered to represent toxic effects, because there were no histopathological correlates indicative of toxicity.
After 5 weeks of treatment at 400 or 1000 mg/kg/day, counts of total white blood cells, neutrophils or monocytes were statistically significantly higher than in concurrent controls in both sexes and basophil counts in females. In addition, prothrombin clotting time was statistically significantly higher than in concurrent controls in males treated at 1000 mg/kg/day and females at 400 or 1000 mg/kg/day. Mean corpuscular volume was marginally lower than in concurrent controls in males at 1000 mg/kg/day.
Alanine aminotransferase and aspartate aminotransferase were statistically significantly higher than in concurrent controls in both sexes at 400 and 1000 mg/kg/day, and urea in males at 400 mg/kg/day and both sexes at 1000 mg/kg/day. In addition albumin to globulin ratio was lower than in concurrent controls in both sexes at 1000 mg/kg/day. Females given 1000 mg/kg/day also had low levels of total protein, albumin, total bilirubin and calcium, and high levels of phosphorus and bile acids all of which attaining statistical significance when compared to concurrent controls.
ORGAN WEIGHTS
After 5 weeks of treatment at 1000 mg/kg/day, prostate and seminal vesicle weights were statistically significantly lower than in concurrent controls. The toxicological significance of this finding remained unclear. Any other organ weights or organ weights adjusted to terminal bodyweight statistically significantly different from concurrent controls did not have any histopathological correlates and were not considered to be indicative of toxicity.
GROSS PATHOLOGY AND HISTOPATHOLOGY (NON-NEOPLASTIC)
The effects on prostate and seminal vesicle weights were consistent with small prostates and small seminal vesicles macroscopically apparent and reduced colloid microscopically seen in these tissues in four of ten high dose males. The toxicological significance of this finding remained unclear.
Thickening of the jejunum, ileum and duodenum was macroscopically apparent in a number of animals from all test item treated groups and thickening of the colon in two of ten males of the high dose group (1000 mg/kg/day) after 5 weeks of treatment, and were attributed to treatment with the test material. Histopathology revealed foamy macrophages within the villi of the illeum and jejunum (at 150, 400 and 1000 mg/kg/day) and of the duodenum (at 400 and 1000 mg/kg/day). Macrophage aggregates in the mesenteric lymph nodes in all treated groups were considered to be secondary deposits of the foamy macrophages seen in the intestines. These pathology findings were considered not to represent toxicity, but to result from test material ingestion by macrophages.
An increased incidence of aggregations of alveolar macrophages in the lungs in both sexes at 1000 mg/kg/day has been of uncertain relationship to treatment. As this is a commonly observed background finding, it is probably fortuitous.
OTHER RESULTS
Reproductive and developmental toxicity parameters are addressed in separate endpoints. - Dose descriptor:
- NOAEL
- Effect level:
- > 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Reduced bodweight gain at 400 and 1000 mg/kg bw/day.
- Dose descriptor:
- NOAEL
- Effect level:
- > 400 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Bodweight gain in dams at 1000 mg/kg bw/day significantly lower than in concurrent controls during gestation, whilst unaffected in nulliparous females during the first five weeks of treatment.
- Critical effects observed:
- not specified
- Conclusions:
- The NOAELs of 150 mg/kg bw/day for male and 400 mg/kg bw/day for female rats were derived from bodyweight gain statistically significantly lower than in concurrent controls in males after 5 weeks of treatment at 400 and 1000 mg/kg bw/day and in dams during gestation at 1000 mg/kg bw/day. These findings were considered to represent adverse effects indicative of toxicity.
Microscopically visible foamy macrophages in the villi of the ileum, jejunum and duodenum and macrophage aggregates in the mesenteric lymph nodes were considered not to reflect a toxic effect of treatment, but to result from ingestion of the test material by macrophages. Possibly the presence of the foamy macrophages in the villi inhibited food consumption and/or nutrient absorption and thus caused reduced bodyweight gain.
Reference
Table 2: Bodyweight and Bodyweight Change - Group Mean Values (g) for Main and Toxicity Phase Animals – Males |
|||||||||||||||||||
Group |
1 |
2 |
3 |
4 |
|||||||||||||||
Compound |
Vehicle Control |
WS400107 |
WS400107 |
WS400107 |
|||||||||||||||
Dose (mg/kg/day) |
0 |
150 |
400 |
1000 |
|||||||||||||||
|
|
|
|||||||||||||||||
Group/Sex |
Week |
Week |
Week |
Week |
Week |
Week |
Change |
Change |
Change |
Change |
Change |
Change |
|||||||
|
0 |
1 |
2 |
3 |
4 |
5 |
0-1 |
1-2 |
2-3 |
3-4 |
4-5 |
0-5 |
|||||||
Statistical test: |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
Wi |
|
|
Wi |
Wi |
|||||||
1/M |
Mean |
371 |
408 |
439 |
455 |
480 |
497 |
37 |
31 |
16 |
25 |
17 |
125 |
||||||
|
SD |
18.9 |
22.9 |
30.9 |
30.3 |
34.0 |
39.3 |
7.2 |
9.0 |
10.8 |
8.1 |
7.6 |
26.1 |
||||||
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||||||
2/M |
Mean |
365 |
396 |
427 |
440 |
462 |
475 |
31 |
31 |
14 |
21 |
13 |
110 |
||||||
|
SD |
15.3 |
18.8 |
24.7 |
28.3 |
30.7 |
32.0 |
6.1 |
8.1 |
8.9 |
7.5 |
7.1 |
19.6 |
||||||
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|||||
3/M |
Mean |
376 |
405 |
431 |
441 |
463 |
465 |
29* |
25 |
11 |
22 |
3** |
89** |
||||||
|
SD |
14.8 |
16.8 |
20.6 |
21.5 |
22.3 |
25.4 |
6.8 |
6.7 |
13.8 |
10.5 |
9.3 |
18.1 |
||||||
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||||||
4/M |
Mean |
369 |
382* |
389** |
396** |
402** |
400** |
13** |
7** |
6 |
6** |
-2** |
31** |
||||||
|
SD |
24.4 |
26.7 |
27.4 |
36.9 |
37.9 |
39.8 |
4.9 |
9.5 |
14.7 |
12.3 |
12.7 |
29.7 |
||||||
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Statistical test Wi = Treated groups compared to Control using Williams’ test, * p<0.05, ** p<0.01
Table 3: Bodyweight and Bodyweight Change - Group Mean Values (g) for Main and Toxicity Phase Animals – Females |
||||||||||||
Group |
1 |
2 |
3 |
4 |
||||||||
Compound |
Vehicle Control |
WS400107 |
WS400107 |
WS400107 |
||||||||
Dose (mg/kg/day) |
0 |
150 |
400 |
1000 |
||||||||
|
||||||||||||
Group/Sex |
Week |
Week |
Week |
Week |
Week |
Week |
|
Change |
Change |
Change |
||
|
0 |
1 |
2 |
3‡ |
4‡ |
5‡ |
|
0-2 |
2-5‡ |
0-5‡ |
||
Statistical test: |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
Sh |
Wi |
Wi |
||
1/F |
Mean |
252 |
265 |
276 |
301 |
306 |
312 |
|
24 |
24 |
55 |
|
|
SD |
13.6 |
15.7 |
23.1 |
37.0 |
38.8 |
41.8 |
|
14.0 |
17.5 |
33.1 |
|
|
N |
15 |
15 |
15 |
6$ |
6$ |
6$ |
|
15 |
6$ |
6$ |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
2/F |
Mean |
252 |
259 |
269 |
291 |
296 |
300 |
|
17 |
20 |
39 |
|
|
SD |
14.4 |
13.6 |
13.0 |
18.0 |
19.7 |
20.1 |
|
6.5 |
6.6 |
12.5 |
|
|
N |
15 |
15 |
15 |
5 |
5 |
5 |
|
15 |
5 |
5 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
3/F |
Mean |
257 |
265 |
273 |
280 |
283 |
285 |
|
16 |
13 |
31 |
|
|
SD |
12.5 |
12.7 |
13.8 |
18.6 |
18.1 |
17.2 |
|
8.5 |
4.4 |
12.9 |
|
|
N |
15 |
15 |
15 |
5 |
5 |
5 |
|
15 |
5 |
5 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
4/F |
Mean |
250 |
263 |
273 |
293 |
302 |
307 |
|
23 |
19 |
52 |
|
|
SD |
13.2 |
14.3 |
15.7 |
7.2 |
12.9 |
14.6 |
|
15.8 |
5.8 |
12.9 |
|
|
N |
15 |
15 |
15 |
6^ |
5 |
5 |
|
15 |
5 |
5 |
|
|
|
|
|
|
|
|
|
|
|
|
|
‡ Toxicity phase animals only
Statistical test Wi = Treated groups compared to Control using Williams’ test, * p<0.05, ** p<0.01
Statistical test Sh Treated groups compared to Control using Shirley’s test, * p<0.05, ** p<0.01
$ One Group 1 female (1F, 65) failed to mate and therefore remained in the treatment phase
^ One Group 4 female (4F, 43) was still in pairing during Week 3
Table 4: Bodyweight and Bodyweight Change - Group Mean Values (g) for Main Phase Females during Gestation |
||||||||||||
Group |
1 |
2 |
3 |
4 |
||||||||
Compound |
Vehicle Control |
WS400107 |
WS400107 |
WS400107 |
||||||||
Dose (mg/kg/day) |
0 |
150 |
400 |
1000 |
||||||||
|
||||||||||||
Group/Sex |
Day |
Day |
Day |
Day |
|
Change |
Change |
Change |
Change |
|||
|
0 |
6 |
13 |
20 |
|
0-6 |
6-13 |
13-20 |
0-20 |
|||
Statistical test: |
Wi |
Wi |
Wi |
Wi |
|
|
Wi |
Wi |
Wi |
|||
1/F |
Mean |
274 |
300 |
337 |
431 |
|
26 |
37 |
94 |
157 |
||
|
SD |
13.2 |
14.3 |
12.1 |
22.1 |
|
8.1 |
6.4 |
12.7 |
13.4 |
||
|
N |
9 |
9 |
9 |
9 |
|
9 |
9 |
9 |
9 |
||
|
|
|
|
|
|
|
|
|
|
|
||
2/F |
Mean |
269 |
295 |
325 |
412 |
|
26 |
30 |
87 |
142 |
||
|
SD |
7.9 |
8.8 |
12.1 |
20.4 |
|
7.0 |
7.2 |
15.2 |
21.2 |
||
|
N |
10 |
10 |
10 |
10 |
|
10 |
10 |
10 |
10 |
||
|
|
|
|
|
|
|
|
|
|
|
||
3/F |
Mean |
272 |
299 |
330 |
418 |
|
27 |
31 |
88 |
146 |
||
|
SD |
11.7 |
11.3 |
14.0 |
20.8 |
|
7.2 |
9.5 |
11.1 |
15.7 |
||
|
N |
10 |
10 |
10 |
10 |
|
10 |
10 |
10 |
10 |
||
|
|
|
|
|
|
|
|
|
|
|
||
4/F |
Mean |
270 |
295 |
320** |
396** |
|
25 |
25** |
76 |
126* |
||
|
SD |
10.5 |
11.1 |
11.1 |
39.5 |
|
7.2 |
8.7 |
30.3 |
37.7 |
||
|
N |
9 |
9 |
9 |
9 |
|
9 |
9 |
9 |
9 |
||
|
|
|
|
|
|
|
|
|
|
|
Statistical test Wi = Treated groups compared to Control using Williams’ test, * p<0.05, ** p<0.01
Table 5: Bodyweight and Bodyweight Change - Group Mean Values (g) for Main Phase Females during Lactation |
|||||||
Group |
1 |
2 |
3 |
4 |
|||
Compound |
Vehicle Control |
WS400107 |
WS400107 |
WS400107 |
|||
Dose (mg/kg/day) |
0 |
150 |
400 |
1000 |
|||
|
|||||||
Group/Sex |
Day |
Day |
Day |
|
Change |
||
|
1 |
4 |
7 |
|
1-7 |
||
Statistical test: |
Wi |
Wi |
Wi |
|
Wi |
||
1/F |
Mean |
334 |
340 |
357 |
|
23 |
|
|
SD |
15.1 |
21.4 |
11.8 |
|
9.9 |
|
|
N |
9 |
9 |
9 |
|
9 |
|
|
|
|
|
|
|
|
|
2/F |
Mean |
321 |
325 |
348 |
|
27 |
|
|
SD |
12.3 |
18.9 |
18.5 |
|
15.7 |
|
|
N |
10 |
10 |
10 |
|
10 |
|
|
|
|
|
|
|
|
|
3/F |
Mean |
312** |
328 |
344 |
|
32 |
|
|
SD |
12.3 |
11.6 |
14.0 |
|
13.4 |
|
|
N |
10 |
10 |
10 |
|
10 |
|
|
|
|
|
|
|
|
|
4/F |
Mean |
307** |
316** |
330** |
|
23 |
|
|
SD |
20.4 |
17.8 |
16.3 |
|
12.5 |
|
|
N |
9 |
9 |
9 |
|
9 |
|
|
|
|
|
|
|
|
Statistical test Wi = Treated groups compared to Control using Williams’ test, * p<0.05, ** p<0.01
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 150 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
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
Additional information
Justification for classification or non-classification
Based on the NOAEL of 150 mg/kg bw/day derived from adverse effects on bodyweight gain in the present study, WS400107 does not need to be classified regarding repeated dose toxicity according to the dangerous substance directive [DIRECTIVE 67/548/EEC ]. WS400107 does also not need to be classified according to the CLP regulation [REGULATION (EC) 1272/2008], because organ toxicity was not evident in the present study.
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