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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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: 469-070-1 | CAS number: 17861-60-8
- 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
In a repeated dose toxicity study performed according to OECD 407 and GLP principles, a NOAEL of 50 mg/kg bw/day was determined for 3-ethylheptamethyltrisiloxane.
.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 5 July 2005 to 13 December 2005
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 1995
- Deviations:
- yes
- Remarks:
- refer to "Overall Remarks" below
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Storage: room temperature
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Strain and species commonly used in repeatd dose toxicity studies
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Species: Rat
Strain: HsdBr1:WH: Wistar
Age: 7-9 weeks
Weight at dosing: M: 154-181g; F: 196-230g
Source: Harlan Winkelmann
Acclimation period: 7 days
Diet: Altromin 1324 maintenance diet for rats and mice, ad libitum
Water: Municpal drinking water ad libitum
Housing: Macrolon cages on Altromin saw fiber bedding. No. of animals house together not stated.
Environmental conditions -
Temperature: 19-25°C
Humidity: 45-65%
Air changes: 10 changes/hr
Photoperiod: 12 hr light/dark - Route of administration:
- oral: gavage
- Details on route of administration:
- orally administered via gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- Method of administration:
Gavage of a suspension, using a stomach tube - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test item was dissolved in corn oil. The vehicle was chosen due to its non-toxic characteristics.
The single dosages (vigorously shaken) were prepared on every application day in the following ratios:
The test item was dissolved in corn oil at a ratio of 0.2 g to 20 mL.
Medium Dose (250 mg/kg bw): The test item was suspended in corn oil at a ratio of 1.0 g to 20 mL.
High Dose (1000 mg/kg bw): The test item was suspended in corn oil at a ratio of 4.0 g to 20 mL.
The homogeneity of the preparations was visually checked. During the application procedure no obvious separation was detected. Analysis of stability and homogeneity was performed and confirmed to be stable. Homogeneity analysis confirmed that mean recovery rates of 109 and 107% of nominal for the low and high dose groups respectively. Concentration analysis confirmed that mean recovery rates of 110, 108 and 106% of nominal for the low, mid and high dose groups respectively. - Duration of treatment / exposure:
- Test duration: 28 days
- Frequency of treatment:
- once daily for 28 consecutive days
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 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:
- 5 animals/sex/group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Animals were randomly allocated to groups using a validated computer system. Each group consisted of 5 animals/sex. Y-14877 was dosed orally via gavage at 0, 50, 250 or 1000 mg/kg bw/d once daily for 28 days, employing a dose volume of 5 mL/kg bw. At necropsy selected organs were weighed and selected tissues were preserved for possible subsequent histological examination.
- Positive control:
- not applicable
- Observations and examinations performed and frequency:
- Observations: Animals were observed at least once a day for clinical observations and at least once daily for morbidity and mortality.
Body weight: Body weight was recorded individually for all rats prior to first application (day 0) and once a week thereafter (day 7, 14, 21, 27).
Food consumption: Calculated weekly (day 7, 14, 21, 27)
Behaviour/functional observation: Once before the first exposure and in the fourth exposure week sensory reactivity to stimuli of different types (e.g. auditory, visual and
proprioceptive stimuli, and motor activity assessment) was conducted.
- Home cage observation: parameters assessed - posture, palpebral closure, and the presence of convulsions or tremors. The rat's reactivity to removal from the cage and handling were then rated and the observer noted presence of salivation, lacrimation, and piloerection.
- Open field: each rat was placed on a table surrounded by a 10 cm cardboard rim for 3 minutes during which time the arousal level (alertness) and gait characteristics were recorded. The number of rears, supported (using the cardboard rim as support) and unsupported (unassisted), were counted separately. In addition, fecal boluses and pools of urine were counted. The presence of convulsions and tremors was again noted.
Reactions to the approach of a pencil, touch on the rump, and tail pinch using forceps were noted. The pupillary response was tested with the aid of a red light using a penlight stimulus.
Flexion reflex, equilibrium, grasping reflex (together with grip strength), righting reflexes and auditory startle were tested. Finally the rectal body temperature was taken
Ophthalmological examination: Not undertaken - Sacrifice and pathology:
- All animals were euthanised by carbon dioxide asphyxiation and subjected to full gross necropsy.
Histopathology was conducted on control and high dose group animals. The following tissues were examined:
All gross lesions, brain (representative regions including cerebrum, cerebellum and pons), spinal cord, liver, kidneys, adrenals, stomach, intestine (small + large, including Peyer's patches, Lymph nodes acc. to application), thymus, thyroid, spleen, lung (+trachea), heart, gonads, accessory sex organs (e.g. uterus, prostate, seminal vesicles), urinary bladder, lymph nodes (Lymphocentrum mandibulare; Lnn axillares), peripheral nerve, bone marrow.
Additionally liver, stomach and thyroids were evaluated from all animals in the low and middle dose groups and kidneys from all male animals in the low and middle dose groups.
Organ weights: The adrenals, adrenals, brain, epididymides, heart, kidneys, liver, spleen, testes, thymus of each animal were weighed. - Other examinations:
- Haematology and clinical chemistry: Blood was collected at necropsy via abdominal aorta puncture:
- Haematology: red blood cell parameters (haematocrit, haemoglobin concentration, erythrocyte count, platelet count), white blood cell parameters (total and differential (neutrophils, lymphocytes, eosinophils, basophils, monocytes, normoblasts) leukocyte count), clotting parameters (platelet count, prothrombin, activated partial thromboplastin time).
- Clinical chemistry: electrolytes (sodium, potassium, urea, creatinine), glucose, liver function tests (alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST)), lipid profile (cholesterol).
Urinalysis: The urine was collected into plain tubes by puncture of the urine bladder as a part of the necropsy the following parameters were examined:
The following urinary parameters were measured: specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, nitrite, leucocytes, erythrocytes - Statistics:
- One-way analysis of variance (ANOVA) was carried out, followed by Student's t-test to reveal any differences between control and test groups
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Clinical signs of toxicity: No treatment related signs of clinical signs of toxicity were observed
- Mortality:
- no mortality observed
- Description (incidence):
- Mortality All animals survived up to the scheduled necropsy
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No relevant significant deviation in weight gain was found (on the 95% confidential level).
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects on food consumption.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Description (incidence and severity):
- Ophthalmoscopic examination: Not applicable as no examinations were undertaken.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No test article related changes in haematological parameters were observed. With the exception of single borderline values (haematocrit, APTT, PTT), almost all individual and mean values were within the expected ranges. The single deviations were considered to be incidental and not toxicologically relevant.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- With the exception of the glucose values, all mean and most individual values were within the expected range. Statistically significant differences were found between some dose groups and the corresponding control groups both in male and female animals. As none of the mean and individual values showed marked pathological deviations, significant differences in general represent variation within a normal range and are of no toxicological relevance (refer to Table CA 7.5.1/01-2).
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Functional and behavioural examination: No differences were observed prior to application and during the last week of dosing.
- Home cage observations: No abnormalities were recorded
Open field: No convulsions, tremors, stereotypy or bizarre behaviour were observed. Animals were used to handling during week 4 as it could be expected.
For supported and unassisted rears no abnormalities were detected.
Responses to reflex testing were normal in all groups.
On measures such as counts of urination and defecation differences could not be detected, since most of the rats displayed none of these activities even under baseline conditions.
Body temperatures were within normal ranges prior to dosing and during week 4. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Test article related effects (refer to Table CA 7.5.1/01-3):
- Liver: mean absolute and relative liver weight in all mid and high dose was increased compared to the weight in the corresponding control group, reaching statistical significance (p<0.05) for the absolute and relative values of the mid and high dose groups of both sexes and the absolute values of the male low dose group.
- Kidney: mean absolute and relative kidney weight in male mid and high dose was slightly increased compared to the weight in the corresponding control group, reaching statistical significance (p<0.05) for the absolute and relative values of the high dose group and the absolute value of the mid dose group. These effects correlated with hyaline droplet formation.
Calculated significant decrease was found for the absolute values of the female low dose group.
Non-test article related effects (these effects did not correlate with any associated histopathological findings in the representative tissues)
- Spleen: mean absolute and relative spleen weight in all dosed groups was slightly increased compared to the weight in the corresponding control group, reaching statistical significance (p<0.05) for the absolute value of the male low dose group.
- Adrenals: mean absolute adrenal weight in the male high dose group was slightly higher than the adrenal weight in the corresponding control group, reaching statistical significance (p<0.05).
- Thymus: mean absolute and relative thymus weight in the female high dose group was slightly decreased compared to the weight in the corresponding control group, reaching statistical significance (p<0.05). Calculated significant increase was found for the absolute values of the male low dose group.
Heart: mean relative heart weight in all dosed male groups, the absolute values in the female low dose and mid dose groups were slightly diminished compared to the heart weight in the corresponding control groups, reaching statistical significance (p<0.05). - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Marked hepatomegaly in all animals of both sexes in the high dose group and slight hepatomegaly in animals of both sexes in the mid-dose group.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment related histopathological findings included (refer to Table CA 7.5.1/01-4):
- Liver: minimal to mild centrilobular hypertrophy was noted in all treated animals of each sex, being graded as minimal in all except 1/5 male and 1/5 given 1000 mg/kg bw/d where the change was mild. Minimal pigment plugs in the periportal bile ducts were noted in 1/5 males from each group given 250 or 1000 mg/kg bw/d. Staining for bile pigments was negative. These effects accounted for the hepatomegaly and higher organ weights which were noted principally at 250 and 1000 mg/kgbw/d. No liver enzyme increases or degenerative changes were associated with the hypertrophy, which is possibly due to P450 enzyme induction.
- Kidney: minimal to mild cortical tubular eosinophilic droplets were noted in nearly all treated males at 50, 250 and 1000 mg/kg bw/d with a dose related severity and incidence. These droplets stained positive for hyaline, being graded as moderate in all treated males.
In addition, minimal to moderate basophilic tubules in the kidneys were recorded at a higher severity and/or incidence in the treated groups than in the control groups (1/5, 3/5, 4/5 and 5/5 animals from groups receiving 0, 50, 250 and 1000 mg/kg bw/d, respectively). Granular casts at the corticomedullary junction were noted in 2/5 and 4/5 males given 250 and 1000 mg/kg bw/d, respectively. None of these findings were apparent in the females except for basophilic tubules, which were present at a similar incidence in the control and high dose groups.
Hyaline droplets are eosinophilic homogeneous cytoplasmic droplets that are normally present in the P2 segment of proximal tubule epithelia of young, mature male rats. The droplets represent alpha 2u-globulin sequestered in secondary lysosomes and and a normal occurrence in young male rats. Other changes concurrently seen in association with hyaline droplet accumulation include granular cast formation
- Thyroids: minimal follicular epithelial hypertrophy was noted in males at 50, 250 and 1000 mg/kg bw/d and in the females at 250 and 1000 mg/kg bw/d. Incidence was low but showed a dose relationship in both sexes. The thyroid effects were likely secondary to the liver effects observed, this however was not confirmed.
- Stomach: minimal or mild diffuse acanthosis in the forestomach was recorded in 1/5 males receiving 250 mg/kg bw/d and in 3/5 males and 4/5 females given 1000 mg/kg bw/d, with a dose-related increase in incidence and severity. In one female it was accompanied by mild hyperkeratosis. These effects are likely to be a local effect due to minimal irritant effect of the test article at the site of first contact. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Details on results:
- refer above
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- Dose descriptor:
- NOEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Basis for effect level:
- other: original NCD unit is mg/kg/day.
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- System:
- hepatobiliary
- Organ:
- liver
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Based on the results of 28-day repeated dose toxicity study, performed according to OECD/EC guidelines and GLP principles, it is concluded that the NOAEL of Y-14877 is 50 mg/kg bw/d (based on increases in both kidney and liver weights, with associated histopathology and histopathological changes in the thyroid at 250 and 1000 mg/kg bw/day).
- Executive summary:
The objective of this study was to evaluate the toxicity of Y-14877 when administered orally via gavage to Wistar rats for 28 days. Y-14877 was administered to groups of 5 male and 5 female rats at dose levels of 0, 50, 250 or 1000 mg/kg bw/d.
There were no unscheduled deaths or clinical signs of toxicity, with no significant deviation in weight gains observed. The functional observational battery confirmed no differences were observed prior to application and during the last week of dosing.
No test article related changes in haematological parameters were observed. With the exception of the glucose values in females, all mean and most individual values were within the expected range.
Test article related effects in organ weights included liver (mean absolute and relative liver weight in all mid and high dose was increased compared to the control group) and kidney (mean absolute and relative kidney weight in male mid and high dose was slightly increased compared to the weight in the corresponding control group, reaching statistical significance) these weight changes were accompanied by histopathological changes. In the liverminimal to mild centrilobular hypertrophy was noted in all treated animals of each sex, minimal pigment plugs in the periportal bile ducts were noted in 1/5 males from each group given 250 or 1000 mg/kg bw/d. Staining for bile pigments was negative. These effects accounted for the hepatomegaly and higher organ weights which were noted principally at 250 and 1000mg/kg bw/d. however, the assessment of P450 upregulation was limited to the blood liver enzyme (ALT, ALP, AST) analysis conducted at necropsy, rather than relevant cytochrome P450 activity associated with thyroid insufficiency (EROD, PROD, BROD, T4-UDP-GT, T3-UDP-GT, MUT-GT, HOBI-GT). In the kidney, minimal to mild cortical tubular eosinophilic droplets were noted in nearly all treated males at 50, 250 and 1000 mg/kg bw/d with a dose related severity and incidence. These droplets stained positive for hyaline, being graded as moderate in all treated males. In addition, minimal to moderate basophilic tubules in the kidneys were recorded at a higher severity and/or incidence in the treated groups than in the control groups. None of these findings were apparent in the females except for basophilic tubules, which were present at a similar incidence in the control and high dose groups. Hyaline droplets are eosinophilic homogeneous cytoplasmic droplets that are normally present in the P2 segment of proximal tubule epithelia of young, mature male rats. The droplets represent alpha 2u-globulin sequestered in secondary lysosomes and a normal occurrence in young male rats and are not deemed relevant for humans.
Other test article related histopathology findings were seen in the thyroid gland (minimal follicular epithelial hypertrophy was noted in males at 50, 250 and 1000 mg/kg bw/d and in the females at 250 and 1000 mg/kg bw/d. Incidence was low but showed a dose relationship in both sexes. The thyroid effects were likely secondary to the liver effects observed, this however was not confirmed), and stomach (minimal or mild diffuse acanthosis in the forestomach was recorded in 1/5 males receiving 250mg/kg bw/d and in 3/5 males and 4/5 females given 1000 mg/kg bw/d, with a dose-related increase in incidence and severity. In one female it was accompanied by mild hyperkeratosis. These effects are likely to be a local effect due to minimal irritant effect of the test article at the site of first contact.)
Based on the results obtained, it is concluded that Y-14877 produced toxicity at dose levels of 250 and 1000 mg/kg bw/d when administered orally via gavage for 28 consecutive days in Wistar rats under the conditions and procedures followed in the present study (based on increases in both kidney and liver weights, with associated histopathology and histopathological changes in the thyroid). There was no evidence of toxicity at 50 mg/kg bw/d and this is considered to be a NOAEL.
Thyroid changes observed (follicular epithelial hypertrophy) were attributed to a secondary effect of liver hypertrophy by the report authors. However, it was concluded that the observed liver hypertrophy was not attributable to liver enzyme induction. In the absence of mode of action work to confirm the biological relevance of the changes in thyroid histopathology observed, it cannot be concluded with certainty that these effects are not attributable to an endocrine mediation action.
Reference
Table CA 7.5.1/01-1:
Overview of 28 day toxicity in rats dosed orally (via gavage) with Y-14877: selected haematology parameters
Parameters | M (mg/kg bw/d) | F (mg/kg bw/d) | |||||||
0 | 50 | 250 | 1000 | 0 | 50 | 250 | 1000 | ||
Hb (g/dL) | 15.34 | 16.24 | 17.30 | 15.40 | 16.78 | 15.04 | 14.88 | 15.58 | |
HbCt (%) | 48.78 | 50.30 | 52.37 | 51.40 | 51.65 | 46.27 | 43.54* | 46.59 | |
WBC (x103uL) | 7.11 | 7.43 | 6.95 | 7.72 | 3.76 | 4.79 | 4.65 | 4.35 | |
APTT (sec) | 15.59 | 17.82 | 17.26 | 16.46 | 19.62 | 19.32 | 18.51 | 16.95* | |
PTT (sec) | 34.52 | 40.13 | 34.73 | 34.50 | 42.87 | 38.12 | 38.19 | 30.49* | |
*: p=0.05 | |||||||||
HbCt: haematocrit | PT: prothrombin time | ||||||||
|
|
|
|
|
|
|
|
|
|
Table CA 7.5.1/01-2:
Overview of 28 day toxicity in rats dosed orally (viagavage) with Y-14877: selected clinical chemistry parameters
Parameters | M (mg/kg bw/d) | F (mg/kg bw/d) | |||||||
0 | 50 | 250 | 1000 | 0 | 50 | 250 | 1000 | ||
ALT (U/I) | 26.68 | 26.40 | 22.62 | 25.82 | 22.06 | 18.70* | 23.22 | 24.22 | |
Chol (mmol/L) | 0.79 | 0.72 | 0.66 | 0.66 | 0.73 | 0.78 | 1.00* | 1.27* | |
TP (g/L) | 52.26 | 54.46 | 56.08 | 57.40* | 56.68 | 57.82 | 61.76* | 62.68* | |
Glucose (mmol/L) | 14.54 | 12.63 | 12.22 | 16.09 | 9.49 | 11.97* | 11.73* | 13.37* | |
Na (mmol/L) | 139.80 | 143.20 | 143.60* | 143.00 | 136.80 | 139.80 | 138.80 | 137.40 | |
K (mmol/L) | 4.92 | 4.35 | 3.99* | 4.78 | 3.85 | 3.89 | 3.70 | 3.63 | |
*: p=0.05 | |||||||||
ALT: alanine aminotransferase | Na: sodium K: potassium | ||||||||
Table CA 7.5.1/01-3:
Overview of 28 day toxicity in rats dosed orally (viagavage) with Y-14877: selected organ weight data
Parameters | M (mg/kg bw/d) | F (mg/kg bw/d) | ||||||
0 | 50 | 250 | 1000 | 0 | 50 | 250 | 1000 | |
Terminal b.w. g | 298.60 | 321.80 | 320.60 | 307.60 | 208.80 | 203.60 | 206.80 | 205.00 |
Liver (abs) g | 8.65 | 9.91* | 12.09* | 15.82* | 6.64 | 6.95 | 9.18* | 13.00* |
Liver (rel) | 3.13 | 3.19 | 3.91* | 5.27* | 3.26 | 3.53 | 4.49* | 6.36* |
Kidney (abs) g | 1.99 | 2.22 | 2.42* | 2.61* | 1.53 | 1.37* | 1.48 | 1.55 |
Kidney (rel) | 0.70 | 0.72 | 0.78 | 0.87* | 0.75 | 0.70 | 0.73 | 0.76 |
*: p=0.05 Abs: Absolute weight |
Table CA 7.5.1/01-4:
Overview of 28 day toxicity in rats dosed orally (viagavage) with Y-14877: selected histopathology data
Parameters | M (mg/kg bw/d) | F(mg/kg bw/d) | ||||||
0 | 50 | 250 | 1000 | 0 | 50 | 250 | 1000 | |
Liver [decedents, incidence/total number examined [minimal, mild, moderate, marked]] | ||||||||
Centrilobular hypertrophy | 0,0/5 | 0,5/5 | 0,5/5 | 0,5/5 | 0,0/5 | 0,5/5 | 0,5/5 | 0,5/5 |
Focal mononuclear cell infiltrate | 0,4/5 | 0,4/5 | 0,3/5 | 0,4/5 | 0,0/5 | 0,5/5 | 0,5/5 | 0,4/5 |
Kidney [decedents, incidence/total number examined [minimal, mild, moderate, marked]] | ||||||||
Basophilic tubules | 0,1/5 | 0,3/5 | 0,4/5 | 0,5/5 | 0,1/5 | - | - | 0,2/5 |
Corticomedullary junction – granular casts | 0,0/5 | 0,0/5 | 0,2/5 | 0,4/5 | - | - | - | - |
Cortical tubular eosinophilic droplets | 0,0/5 | 0,5/5 | 0,5/5 | 0,5/5 | - | - | - | - |
Presence of a-2u globulin | 0,0/5 | 0,5/5 | 0,5/5 | 0,4/5 | - | - | - | - |
Thyroid [decedents, surviving/total number [minimal, mild, moderate, marked]] | ||||||||
Follicular epithelial hypertrophy | 0,0/5 | 0,1/5 | 0,2/5 | 0,3/5 | 0,0/5 | 0,0/5 | 0,1/5 | 0,2/5 |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 50 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
Mode of Action Analysis / Human Relevance Framework
The objective of this study was to evaluate the toxicity of Y-14877 when administered orally via gavage to Wistar rats for 28 days. Y-14877 was administered to groups of 5 male and 5 female rats at dose levels of 0, 50, 250 or 1000 mg/kg bw/d.
There were no unscheduled deaths or clinical signs of toxicity, with no significant deviation in weight gains observed. The functional observational battery confirmed no differences were observed prior to application and during the last week of dosing.
No test article related changes in haematological parameters were observed. With the exception of the glucose values in females, all mean and most individual values were within the expected range.
Test article related effects in organ weights included liver (mean absolute and relative liver weight in all mid and high dose was increased compared to the control group) and kidney (mean absolute and relative kidney weight in male mid and high dose was slightly increased compared to the weight in the corresponding control group, reaching statistical significance) these weight changes were accompanied by histopathological changes. In the liverminimal to mild centrilobular hypertrophy was noted in all treated animals of each sex, minimal pigment plugs in the periportal bile ducts were noted in 1/5 males from each group given 250 or 1000 mg/kg bw/d. Staining for bile pigments was negative. These effects accounted for the hepatomegaly and higher organ weights which were noted principally at 250 and 1000mg/kg bw/d. however, the assessment of P450 upregulation was limited to the blood liver enzyme (ALT, ALP, AST) analysis conducted at necropsy, rather than relevant cytochrome P450 activity associated with thyroid insufficiency (EROD, PROD, BROD, T4-UDP-GT, T3-UDP-GT, MUT-GT, HOBI-GT). In the kidney, minimal to mild cortical tubular eosinophilic droplets were noted in nearly all treated males at 50, 250 and 1000 mg/kg bw/d with a dose related severity and incidence. These droplets stained positive for hyaline, being graded as moderate in all treated males. In addition, minimal to moderate basophilic tubules in the kidneys were recorded at a higher severity and/or incidence in the treated groups than in the control groups. None of these findings were apparent in the females except for basophilic tubules, which were present at a similar incidence in the control and high dose groups. Hyaline droplets are eosinophilic homogeneous cytoplasmic droplets that are normally present in the P2 segment of proximal tubule epithelia of young, mature male rats. The droplets represent alpha 2u-globulin sequestered in secondary lysosomes and a normal occurrence in young male rats and are not deemed relevant for humans.
Other test article related histopathology findings were seen in the thyroid gland (minimal follicular epithelial hypertrophy was noted in males at 50, 250 and 1000 mg/kg bw/d and in the females at 250 and 1000 mg/kg bw/d. Incidence was low but showed a dose relationship in both sexes. The thyroid effects were likely secondary to the liver effects observed, this however was not confirmed), and stomach (minimal or mild diffuse acanthosis in the forestomach was recorded in 1/5 males receiving 250mg/kg bw/d and in 3/5 males and 4/5 females given 1000 mg/kg bw/d, with a dose-related increase in incidence and severity. In one female it was accompanied by mild hyperkeratosis. These effects are likely to be a local effect due to minimal irritant effect of the test article at the site of first contact.)
Based on the results obtained, it is concluded that Y-14877 produced toxicity at dose levels of 250 and 1000 mg/kg bw/d when administered orally via gavage for 28 consecutive days in Wistar rats under the conditions and procedures followed in the present study (based on increases in both kidney and liver weights, with associated histopathology and histopathological changes in the thyroid). There was no evidence of toxicity at 50 mg/kg bw/d and this is considered to be a NOAEL.
Thyroid changes observed (follicular epithelial hypertrophy) were attributed to a secondary effect of liver hypertrophy by the report authors. However, it was concluded that the observed liver hypertrophy was not attributable to liver enzyme induction. In the absence of mode of action work to confirm the biological relevance of the changes in thyroid histopathology observed, it cannot be concluded with certainty that these effects are not attributable to an endocrine mediation action.
Additional information
Justification for classification or non-classification
According to CLP (1272/2008/EC) classification criteria for repeated dose toxicity, no classification is required.
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.