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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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: 221-897-7 | CAS number: 3271-76-9
- 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
Repeated dose toxicity via oral route
NOEL 1000 mg/kg bw in male and female Sprague-Dawley rats (OECD 422)
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
- Study period:
- 27 May 2015 to 10 March 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- 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)
- Deviations:
- yes
- Remarks:
- See below under 'Priniciples of method...'
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 474 adopted on September 2014
- Deviations:
- yes
- Remarks:
- See below under 'Priniciples of method...'
- Principles of method if other than guideline:
- Protocol deviations:
Uterus of the female humanely killed on Day 3 post coitum was not immersed in a 10-20% solution of ammonium sulphide to reveal evidence of implantation
and pregnancy was therefore not established in this animal.
Animal no. 41 was not observed on Day 4 post partum and recovery males and females were not observed on Day 47.
Animals of the positive control group were not weighed prior to sacrifice.
Parturition check for animal no. 3 started on Day 19 of gestation instead of Day 20.
Slides for micronucleus test were not dried overnight as indicated in the study protocol but as necessary to obtain complete dehydration.
These deviations were not considered to have compromised the purpose or conduct of the study.
No other deviations occurred. - GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- A total of 125 Sprague Dawley [Crl:CD(SD)BR] rats (65 males and 60 virgin females), 7 to 8 weeks old and weighing 200 to 225 g for males and 175 to 200 g for females, were ordered from and supplied by Charles River Italia S.p.A., Calco (Lecco), Italy.After arrival, on 21 May 2015, the weight range for each sex was determined (189-216 g for females, 226-250 g for males, slightly outside the range at order) and the animals were temporarily identified within the cage by means of a coloured mark on the tail.A health check was then performed by a veterinarian. An acclimatisation period of at least 14 days was allowed before the start of treatment, during which time the health status of the animals was assessed by thorough observations.The animals were housed in a limited access rodent facility. Animal room controls were set to maintain temperature and relative humidity at 22°C +/- 2°C and 55% +/- 15% respectively; actual conditions were monitored, recorded and the records retained. No relevant deviations from these ranges were recorded during the study.There were approximately 15 to 20 air changes per hour and the rooms were lit by artificial light for 12 hours each day.
- Route of administration:
- oral: gavage
- Details on route of administration:
- The test item was administered orally by gavage at a dose volume of 5 mL/kg body weight. Control animals received the vehicle alone at the same dose volume. The dose was administered to each animal on the basis of the most recently recorded body weight and the volume administered was recorded for each animal.
- Vehicle:
- other: Sesame oil
- Details on oral exposure:
- The required amount of Vat Black 25 was dissolved/suspended in the vehicle. The formulations were prepared daily (concentrations of 12,5, 50 and 200 mg/mL). Concentrations were calculated and expressed in terms of test item as supplied.
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Analysis was not performed to confirm that the proposed formulation procedure was acceptable and that the stability of the formulation was satisfactory as the test item is neither extractable in hydrophilic nor in lipophilic solvents. The correct concentration preparation was monitored in the weighing record of the test item in each formulation process.
- Duration of treatment / exposure:
- Main groups (Groups 1 to 4):
Males:
Animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing, through the mating period and thereafter through the day before necropsy (Days 43 and 44 of study). They were treated for a total of 42 or 43 days. Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
Females:
Animals were dosed once a day, 7 days a week, for 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum (for approximately 42 days). Dose volumes were adjusted once per week for each animal according to the last recorded body weight. During the gestation period, dose volumes were calculated according to individual body weight on Days 0, 7, 14 and 20 post coitum and on Day1 post partum. Thereafter individual dose volumes remained constant.
Recovery groups (Groups 5 and 6):
Animals were dosed once a day, 7 days a week, for a minimum of 6 consecutive weeks. No treatment was given during the recovery period.
Positive Control group (Group 7):
Animals received a single dose of the positive control (for genotoxicity endpoint) approximately 24 hours before sacrifice. - Frequency of treatment:
- Once daily
- Dose / conc.:
- 62.5 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- Each main group comprised 10 male and 10 female rats (Groups 1 to 4). Two groups (control and high dose levels) included 5 animals per sex which were sacrificed after 2 weeks of recovery (Groups 5 and 6). For genotoxicity endpoint, a satellite control group (Positive Control group) comprised 5 male rats (Group 7).
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels have been selected in consultation with the Sponsor based on information from previous studies.
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: A recovery group was included to assess recovery from any delayed toxicity or persistence of adverse effects observed during the dosing phase. In addition, the micronucleus test was included (5 male rats of the main groups) in order to assess the ability of the test item to induce cytogenetic damage in rat bone marrow, as measured by the induction of micronuclei in polychromatic erythrocytes.
- Post-exposure recovery period in satellite groups: 2 weeks - Positive control:
- Positive control treatments for genotoxicity endpoints used the well-known clastogen Mitomycin-C (Sigma-Aldrich, batch no. SLBH9906V, expiry date: January 2018).
- Observations and examinations performed and frequency:
- Main and Recovery groups:
Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical signs were recorded.
Observations were performed at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions (15-45 minutes after treatment).
Observations of the cage tray
Observations of the cage tray were performed during mating period for all main groups and were recorded daily.
Positive Control group
Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical signs were recorded.
Neurotoxicity assessment (removal of animals from the home cage and open arena).
Once before commencement of treatment and at least once per week from the start of treatment until termination, each animal was given a detailed clinical examination. Each animal was removed from the home cage and observed in an open arena (for at least 3 minutes). The test included observation of changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypies or bizarre behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, unusual respiratory pattern). Changes in fur, skin, eyes, mucous membranes, occurrences of secretions and excretions were also recorded.
Grip strength and sensory reaction to stimuli
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group for evaluation of sensory reaction to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli); an assessment of grip strength was also performed. Measurements were performed using a computer generated random order (for the main groups). For males (main groups), the tests were performed on Day 40 of the study and for females on Day 3 post partum (main groups). For animals of the recovery groups, the tests were performed on Day 41 of the study (during treatment) and once during Week 2 of recovery (Day 10).
Motor activity assessment (MA)
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group and the motor activity was measured (for approximately 5 minutes) by an automated activity recording device. Measurements were performed using a computer generated random order (for the main groups). For males (main groups) the tests were performed on Day 41 of the study and for females on Day 3 post partum (main groups). For animals of the recovery groups, the tests were performed on Day 42 of the study (during treatment) and once during Week 2 of recovery (Day 13).
Body weight
Main groups
Males were weighed weekly from allocation to termination. Females were weighed weekly from allocation to positive identification of mating and on Days 0, 7, 14 and 20 post coitum. Dams were also weighed on Days 1 and 4 post partum.
Recovery groups
Each animal was weighed on the day of allocation to treatment groups, on the day that treatment commenced, weekly thereafter and just prior to necropsy.
Positive Control group
Animals were weighed on the day of allocation and on the day of dosing.
Food consumption
Main groups
The weight of food consumed by each cage of males and females was recorded weekly (whenever possible) during the pre-mating period starting from allocation. Individual food consumption for the females was measured on Days 7, 14 and 20 post coitum starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum.
Recovery groups
The weight of food consumed by each cage of rats was recorded at weekly intervals following allocation.
Clinical pathology investigations
During the necropsy procedure, samples of blood were withdrawn under isofluorane anaesthesia from the abdominal vena cava from 5 males and 5 females (females with viable litters) randomly selected from each group under conditions of food deprivation for haematological, coagulation and clinical chemistry evaluations.
The blood samples collected were divided into tubes as follows:
– EDTA anticoagulant for haematological investigations
– Heparin anticoagulant for biochemical tests
– Citrate anticoagulant for coagulation tests
The measurements performed on blood samples are listed below:
-Haematology
– Haematocrit
– Haemoglobin
– Red blood cell count
– Reticulocyte count
– Mean red blood cell volume
– Mean corpuscular haemoglobin
– Mean corpuscular haemoglobin concentration
– White blood cell count
– Differential leucocyte count
Neutrophils
Lymphocites
Eosinophils
Basophils
Monocytes
Large unstained cells
– Platelets
Coagulation
– Prothrombin time
– Activated partial thromboplastin time
Clinical chemistry
– Alkaline phosphatase
– Alanine aminotransferase
– Aspartate aminotransferase
– Gamma-glutamyltransferase
– Urea
– Creatinine
– Glucose
– Triglycerides
– Bile acids
– Inorganic phosphorus
– Total bilirubin
– Total cholesterol
– Total protein
– Albumin
– Globulin
– A/G Ratio
– Sodium
– Potassium
– Calcium
– Chloride - Sacrifice and pathology:
- Main and Recovery groups
One animal, sacrificed for humane reasons, was killed under carbon dioxide asphyxiation. Animals that had completed the scheduled test period and selected for blood collection, were killed by exsanguination under isofluorane anaesthesia. Animals that had completed the scheduled test period and not selected for blood collection, were killed by carbon dioxide asphyxiation.
Positive Control group
Positive Control group animals were killed under carbon dioxide asphyxiation.
Parental males (Main groups)
The males were killed after the mating of all females or after at least 28 days of treatment period.
Parental females (Main groups)
The females with live pups were killed on Day 4 post partum. The females which did not give birth 25 days after positive identification of mating werekilled shortly after.
Males and females (Recovery groups)
Animals were killed after 2 weeks of recovery.
Positive Control group
Animals were killed approximately 24 hours after treatment.
Necropsy (Main and Recovery groups)
The clinical history of adult animals was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices). Changes were noted, the requisite organs weighed (excluding the animal sacrificed for humane reasons) and the required tissue samples preserved in fixative and processed for histopathological examination.
Females (Main groups)
All females were also examined for the following:
– external and internal abnormalities;
– number of visible implantation sites (pregnant animals);
– number of corpora lutea (pregnant animals).
Uteri of apparently non-pregnant females or uteri of females with no visible implantations were immersed in a 20% solution of ammonium sulphide to reveal evidence of implantation.
Organ weights (Main and Recovery groups)
From all animals completing the scheduled test period, the following organs were dissected free of fat and weighed:
Adrenal glands
Brain (cerebrum, cerebellum, medulla/pons)
Epididymides
Heart
Kidneys
Liver
Ovaries with oviducts
Parathyroid glands
Prostate gland
Seminal vesicles with coagulating glands
Spleen
Testes
Thymus
Thyroid
Uterus including cervix
The ratios of organ weight to body weight were calculated for each animal.
Tissues fixed and preserved (Main and Recovery groups)
Samples of all the tissues listed below in were fixed and preserved in 10% neutral buffered formalin (except eyes, optic nerves and Harderian glands, testes and epididymides which were fixed in modified Davidson’s fluid and preserved in 70% ethyl alcohol).
Abnormalities
Adrenal glands
Bone marrow (from sternum)
Brain (cerebrum, cerebellum, medulla/pons)
Caecum
Clitoral gland
Colon
Duodenum
Epididymides
Heart
Ileum (including Peyer’s patches)
Jejunum
Kidneys
Liver
Lungs (including mainstem bronchi)
Lymph nodes – cervical
Lymph nodes – mesenteric
Nasal cavity
*Oesophagus
*Ovaries with oviducts
Parathyroid glands
Pituitary gland
Penis
Prostate gland
Rectum
Sciatic nerve
Seminal vesicles with coagulating glands
Spinal column
*Spinal cord (cervical, thoracic, lumbar)
Spleen
Stomach (forestomach and glandular)
Testes
Thymus (where present)
Thyroid
Trachea
Urinary bladder
Uterus including cervix
Vagina
*not examined as no signs of toxicity or target organ involvement were observed.
After dehydration and embedding in paraffin wax, sections of the tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin. In addition, the testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS).
The morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was also performed.
The examination was restricted as detailed below:
i Tissues specified above from 5 males and 5 females (main groups) randomly selected (animals evaluated for clinical pathology) in the control and high dose group killed at term.
ii Tissues specified above from all animals killed or dying during the treatment period.
iii All abnormalities in all main groups. - Other examinations:
- No data
- Statistics:
- Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data. The nonparametric Kruskal-Wallis analysis of variance (non-continuous variables) was used for the other parameters. Intergroup differences between the control and treated groups was assessed by the non-parametric version of the Williams test. The criterion for statistical significance was p < 0.05.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No signs of toxicological relevance were observed during the study.
Slight orange staining in the cage tray was observed during the mating phase in some cages of mid- and high dose animals.
Observation of animals at removal from the cage and in an open arena did not reveal changes attributable to the test item.
No alterations in motor activity, grip strength and sensory reaction to stimuli were observed in any treatment group at the examination performed at the end of treatment.
At the end of recovery period, motor activity, grip strength and sensory reaction to stimuli were comparable between control and treated groups of both sexes. - Mortality:
- no mortality observed
- Description (incidence):
- One female of the high dose group, receiving 1000 mg/kg bodyweight/day was killed for humane reasons on Day 3 of the gestation phase. On the day of sacrifice, hunched posture and marked swelling of the fore and hind limbs were recorded.
Macroscopic findings observed at post mortem examination in this animal were represented by swollen and oedematous consistency of hindlimbs and right forelimb, as well as unilateral pelvic dilatation.
Marked arthritis of hindlimbs and one forelimb, observed at histopathology, could be considered as a factor contributory to the illness status of the animal sacrificed for humane reasons. Therefore, this death was considered to be unrelated to treatment. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Throughout the study, no difference in body weights was recorded in animals of both sexes compared to the control group.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No effects on food consumption were observed in both sexes.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No relevant changes were observed. The statistically significant differences between controls and treated males (mean corpuscular volume, neutrophils and eosinophils percentages), were of minimal severity and/or not dose-related, therefore considered of no toxicological significance.
Coagulation: no changes were recorded. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No relevant changes were observed. The statistically significant differences recorded (urea, glucose, chloride, phosphorus in males) were not dose-related, therefore considered unrelated to treatment.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Main and recovery groups
Observation of animals at removal from the cage and in an open arena did not reveal changes attributable to the test item.
No alterations in motor activity, grip strength and sensory reaction to stimuli were observed in any treatment group at the examination performed at the end of treatment.
At the end of recovery period, motor activity, grip strength and sensory reaction to stimuli were comparable between the control and treated group in both sexes. - Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Absolute and relative organ weights were comparable in all groups.
The following statistically significant difference was noted in the organ weights of the main groups:
– Decreased relative uterus weight in females receiving 250 and 1000mg/kg body weight/day (-30 % and -25 %, respectively). Absolute uterus weight was also decreased in all groups when compared to controls. This difference was without dose-dependency and not accompanied by histological findings. Therefore, it was considered not to be treatment-related. No toxicological significance was attributed to the other statistically significances observed in the weight of organs. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no compound-related effects.
No relevant changes were noted in study animals sacrificed at the end of the treatment period or after 2 weeks of recovery period.
Changes such as pelvic dilatation, swollen liver and small size of thymus in the control and treated groups, both in final and recovery animals, were considered to be incidental. - Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No microscopic observation was observed in treated animals that could be considered treatment-related.
A limited number of lesions, reported in control and/or treated animals, were considered to be an expression of spontaneous and/or incidental pathology, seen in this species and age of untreated animals.
In addition seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and no alterations were noted. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not specified
- Details on results:
- No signs of genotoxicity were detected by measuring the micronuclei in polychromatic erythrocytes.
No treatment-related effects indicating systemic toxicity were observed in male or female animals at any of the dose levels investigated (0, 62.5, 250 and 1000 mg/kg body weight/day). - Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects of toxicological significance at highest dose tested: 1000 mg/kg bw/day
- Key result
- Critical effects observed:
- no
- Conclusions:
- Based on the results of the present study, the NOEL (No Observed Effect Level) for general toxicity, reproductive and developmental toxicity was considered to be 1000 mg/kg bw/day for males and females.
- Executive summary:
Repeated dose oral toxicity study performed in male & female Sprague-Dawley rats in accordance with OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test).
Male animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing, through the mating period and thereafter through the day before necropsy (Days 43 and 44 of study). They were treated for a total of 42 or 43 days. Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
Females were dosed once a day, 7 days a week, for 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum (for approximately 42 days). Dose volumes were adjusted once per week for each animal according to the last recorded bodyweight. During the gestation period, dose volumes were calculated according to individual body weight on Days 0, 7, 14 and 20 post coitum and on Day 1 post partum. Thereafter individual dose volumes remained constant.
Recovery group animals were dosed once a day, 7 days a week, for a minimum of 6 consecutive weeks. No treatment was given during the recovery period.
Each main group comprised 10 male and 10 female rats. Two groups (control and high dose levels) included 5 animals per sex which were sacrificed after 2 weeks of recovery.
One female of the high dose group, receiving 1000 mg/kg bodyweight/day, was killed for humane reasons on Day 3 of the gestation phase.
Marked arthritis of hind limbs and one forelimb, observed at histopathology, could be considered as a factor contributory to the illness status of the animal sacrificed for humane reasons. Therefore, this death was considered to be unrelated to treatment.
No clinical signs of toxicological relevance or signs of neurotoxicity (weekly observations at removal from the cage and in an open arena, alterations in motor activity, grip strength and sensory reaction to stimuli) were observed during the study in males and females. Slight orange staining in the cage tray was observed during the mating phase in some cages of mid- and high dose animals.
No differences in body weight and food consumption were observed in treated animals compared to the control group.
No changes of toxicological significance were recorded at haematological, clinical chemistry investigations or at coagulation tests in animals sacrificed at the end of the study.
No relevant changes were detected at post mortem examination (terminal body weight, organ weights, macroscopic and microscopic examinations) in treated animals, when compared with controls.
Based on the results of the present study, the NOEL (No Observed Effect Level) for general toxicity was considered to be 1000 mg/kg bw/day for males and females.
Reference
FATE OF FEMALES – GROUP INCIDENCE
Group |
1 |
2 |
3 |
4 |
Initial group size |
10 |
10 |
10 |
10 |
Not pregnant |
0 |
0 |
2 |
0 |
Unilateral implantation |
0 |
1 |
0 |
0 |
Humane killed |
0 |
0 |
0 |
1a |
With live pups on Day 4 post partum |
10 |
10 |
8 |
9 |
a= pregnancy not detected
CLINICAL SIGNS OF MALES – MAIN GROUPS – GROUP INCIDENCE
Interval: 1! – 30” Days Group Observation |
1 (10) |
2 (10) |
3 (10) |
4 (10) |
||||
|
a |
b |
a |
b |
a |
b |
a |
b |
No significant signs |
10 |
38.9 |
10 |
43.5 |
10 |
43.5 |
10 |
42.2 |
APPEARANCE Hair loss |
1 |
30.0 |
0 |
0.0 |
0 |
0.0 |
2 |
6.5 |
EYE – EAR – MOUTH Damaged ear |
1 |
16.0 |
0 |
0.0 |
0 |
0.0 |
0 |
0.0 |
Key: () = Number of animals alive at start of interval
a = Number of animal affected
b = Number of days with clinical sign/animal
Note: ! = Premating phase; “ = Mating phase
CLINICAL SIGNS OF FEMALES BEFORE PAIRING – MAIN GROUPS – GROUP INCIDENCE
Interval: 1 - 15 Days Group Observation |
1 (10) |
2 (10) |
3 (10) |
4 (10) |
||||
|
a |
b |
a |
b |
a |
b |
a |
b |
No significant signs |
10 |
15.0 |
10 |
15.0 |
10 |
15.0 |
10 |
15.0 |
Key: () = Number of animals alive at start of interval
a = Number of animal affected
b = Number of days with clinical sign/animal
CLINICAL SIGNS OF FEMALES –POST COITUMANDPOST PARTUMPERIODS - MAIN GROUPS – GROUP INCIDENCE
Interval: 0! – 4” Days Group Observation |
1 (10) |
2 (10) |
3 (10) |
4 (10) |
||||
|
a |
b |
a |
b |
a |
b |
a |
b |
No significant signs |
10 |
27.1 |
10 |
27.2 |
10 |
27.1 |
10 |
24.1 |
APPEARANCE Cyphosis Swollen |
0 0 |
0.0 0.0 |
0 0 |
0.0 0.0 |
0 0 |
0.0 0.0 |
1 1 |
1.0 1.0 |
Key: () = Number of animals alive at start of interval
a = Number of animal affected
b = Number of days with clinical sign/animal
Note: ! = Gestation phase phase; “ = Postpartum phase
CLINICAL OBSERVATIONS DURING TREATMENT – BEHAVIOURAL EXAMINATION – REMOVAL OF ANIMALS FROM THE HOME CAGE - MAIN GROUPS – GROUP INCIDENCE
MALES
Interval: 1! – 6” Weeks Group Observation |
1 (10) |
2 (10) |
3 (10) |
4 (10) |
||||
|
a |
b |
a |
b |
a |
b |
a |
b |
REMOVAL Removal easy |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
HANDLING REACTIVITY Handling reactivity normal |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
LACHRYMATION Lachrymation absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
PALPEBRAL CLOSURE Palpebral closure absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
SALIVATION Salivation absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
PILOERECTION Piloerection absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
Key: () = Number of animals alive at start of interval
a = Number of animals affected
b = Number of week with clinical sign/animal
Note: ! = Pretest phase; “ = Dosing phase
CLINICAL OBSERVATIONS DURING TREATMENT – BEHAVIOURAL EXAMINATION – REMOVAL OF ANIMALS FROM THE HOME CAGE - MAIN GROUPS – GROUP INCIDENCE
FEMALES
Interval: 1! – 6” Weeks Group Observation |
1 (10) |
2 (10) |
3 (10) |
4 (10) |
||||
|
a |
b |
a |
b |
a |
b |
a |
b |
REMOVAL Removal easy |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
HANDLING REACTIVITY Handling reactivity normal |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
LACHRYMATION Lachrymation absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
PALPEBRAL CLOSURE Palpebral closure absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
SALIVATION Salivation absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
PILOERECTION Piloerection absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
Key: () = Number of animals alive at start of interval
a = Number of animals affected
b = Number of week with clinical sign/animal
Note: ! = Pretest phase; “ = Dosing phase
CLINICAL OBSERVATIONS DURING TREATMENT – BEHAVIOURAL EXAMINATION – OPEN AREA – MAIN GROUPS – GROUP INCIDENCE
MALES
Interval: 1! – 6” Weeks Group Observation |
1 (10) |
2 (10) |
3 (10) |
4 (10) |
||||
|
a |
b |
a |
b |
a |
b |
a |
b |
REARING Rearing absent Rearing 1-3 Rearing 4-7 Rearing 8-10 Rearing 11-14 Rearing 15-20 Rearing 21-30 |
0 2 5 9 10 5 0 |
0.0 1.5 2.6 1.7 3.0 1.8 0.0 |
0 1 4 9 10 5 0 |
0.0 2.0 1.8 2.8 2.8 1.6 0.0 |
1 2 3 8 10 8 0 |
2.0 3.0 1.7 2.0 2.2 2.4 0.0 |
0 1 2 9 10 7 2 |
0.0 1.0 1.0 2.7 2.8 1.9 1.0 |
SPASMS Spasms absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
MYOCLONIA Myoclonia absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
GAIT Normal gait |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
MOBILITY IMPAIRMENT Mobility impairment absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
AROUSAL Arousal normal Arousal slow |
10 0 |
7.0 0.0 |
10 0 |
7.0 0.0 |
10 1 |
6.8 2.0 |
10 0 |
7.0 0.0 |
VOCALISATION Vocalisation absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
STEREOTYPIES Stereotypies absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
UNUSUAL RESPIRATION Unusual respiration absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
BIZARRE BEHAVIOUR Bizarre behaviour absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
URINATION Urination absent Urination 1-3 Urination 4-6 Urination 7-9 Urination more than 10 |
10 8 2 3 0 |
4.0 3.0 1.5 1.0 0.0 |
10 7 6 1 1 |
4.8 1.7 1.2 1.0 2.0 |
10 6 5 0 1 |
5.0 2.2 1.2 0.0 1.0 |
10 7 3 2 0 |
5.1 1.3 2.7 1.0 0.0 |
DEFECATION Defecation absent Defecation 1-3 Defecation 4-6 |
10 6 3 |
4.9 2.5 2.0 |
10 6 3 |
6.0 1.2 1.0 |
10 5 1 |
6.2 1.4 1.0 |
10 6 2 |
5.8 1.7 1.0 |
TREMORS Tremors absent |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
10 |
7.0 |
Key: () = Number of animals alive at start of interval
a = Number of animals affected
b = Number of weeks with clinical sign/animal
Note: ! = Pretest phase; “ = Dosing phase
CLINICAL OBSERVATIONS DURING TREATMENT – BEHAVIOURAL EXAMINATION – OPEN AREA – MAIN GROUPS – GROUP INCIDENCE
FEMALES
Interval: 1! – 6” Weeks Group Observation |
1 (10) |
2 (10) |
3 (10) |
4 (10) |
||||
|
a |
b |
a |
b |
a |
b |
a |
b |
REARING Rearing 11-14 Rearing 15-20 Rearing 21-30 Rearing more than 30 |
5 10 8 4 |
2.2 3.6 2.3 1.3 |
5 10 6 1 |
2.4 3.6 3.2 1.0 |
7 7 6 5 |
1.6 4.4 3.3 1.4 |
6 10 6 1 |
2.7 3.6 2.2 1.0 |
SPASMS Spasms absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
MYOCLONIA Myoclonia absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
GAIT Normal gait |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
MOBILITY IMPAIRMENT Mobility impairment absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
AROUSAL Arousal normal |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
VOCALISATION Vocalisation absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
STEREOTYPIES Stereotypies absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
UNUSUAL RESPIRATION Unusual respiration absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
BIZARRE BEHAVIOUR Bizarre behaviour absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
URINATION Urination absent Urination 1-3 Urination 4-6 Urination 7-9 Urination more than 10 |
10 7 3 1 1 |
5.1 1.7 1.7 1.0 1.0 |
10 6 3 0 0 |
5.6 1.5 1.0 0.0 0.0 |
10 5 5 2 0 |
5.2 1.6 1.4 1.0 0.0 |
10 9 4 0 0 |
4.0 2.1 1.8 0.0 0.0 |
DEFECATION Defecation absent Defecation 1-3 |
10 2 |
6.7 1.0 |
10 3 |
6.5 1.0 |
10 1 |
6.8 1.0 |
10 3 |
6.3 1.0 |
TREMORS Tremors absent |
10 |
6.9 |
10 |
6.8 |
10 |
6.9 |
10 |
6.6 |
Key: () = Number of animals alive at start of interval
a = Number of animals affected
b = Number of weeks with clinical sign/animal
Note: ! = Pretest phase; “ = Dosing phase
BODY WEIGHT (g) OF MALES – BEFORE PAIRING – MAIN GROUPS – GROUP MEAN DATA
Group(s) |
|
Day of Phase |
|||
1! |
1” |
8 |
15# |
||
1 |
(n) Mean SD |
10 291.27 8.04 |
10 351.93 14.40 |
10 391.82 19.31 |
10 418.66 24.10 |
2 |
(n) Mean SD |
10 290.91 6.82 |
10 343.76 11.97 |
10 375.38 16.31 |
10 400.39 20.38 |
3 |
(n) Mean SD |
10 290.21 8.48 |
10 344.05 15.02 |
10 378.62 15.50 |
10 404.02 17.39 |
4 |
(n) Mean SD |
10 291.32 7.25 |
10 351.16 12.67 |
10 387.61 16.39 |
10 416.80 17.10 |
Note: ! = Pretest phase; “ = Premating phase; # = Start of pairing phase
* = mean value of group is significantly different from control at p<0.05
** = mean value of group is significantly different from control at p<0.01
Statistical analysis:Dunnett’s test if group variances are homogenous
Modified t test is group variances are inhomogenous ($)
BODY WEIGHT (g) OF MALES – FROM PAIRING PERIOD TO SACRIFICE – MAIN GROUPS – GROUP MEAN DATA
Group(s) |
|
Day of Phase |
|||
8 |
15 |
22 |
29 |
||
1 |
(n) Mean SD |
10 440.52 28.74 |
10 463.91 35.21 |
10 484.62 32.37 |
10 491.88 43.22 |
2 |
(n) Mean SD |
10 424.16 21.21 |
10 445.27 27.57 |
10 467.04 31.46 |
10 474.21 35.30 |
3 |
(n) Mean SD |
10 424.73 19.19 |
10 449.58 19.40 |
10 470.60 23.64 |
10 479.52 34.21 |
4 |
(n) Mean SD |
10 436.14 16.77 |
10 463.39 22.11 |
10 484.57 21.84 |
10 492.04 28.45 |
Note: Data for Mating phase
* = mean value of group is significantly different from control at p<0.05
** = mean value of group is significantly different from control at p<0.01
Statistical analysis:Dunnett’s test if group variances are homogenous
Modified t test is group variances are inhomogenous ($)
BODY WEIGHT (g) OF FEMALES – BEFORE PAIRING – MAIN GROUPS – GROUP MEAN DATA
Group(s) |
|
Day of Phase |
|||
1! |
1” |
8 |
15# |
||
1 |
(n) Mean SD |
10 214.83 8.35 |
10 236.18 5.69 |
10 242.60 6.15 |
10 2.53.35 12.29 |
2 |
(n) Mean SD |
10 215.15 9.37 |
10 234.15 8.25 |
10 239.03 15.65 |
10 253.72 14.16 |
3 |
(n) Mean SD |
10 214.46 8.79 |
10 235.66 8.48 |
10 244.87 12.84 |
10 256.33 12.30 |
4 |
(n) Mean SD |
10 214.42 8.98 |
10 231.99 9.54 |
10 243.20 9.19 |
10 254.36 12.53 |
Note: ! = Pretest phase; “ = Premating phase; # = Start of pairing phase
* = mean value of group is significantly different from control at p<0.05
** = mean value of group is significantly different from control at p<0.01
Statistical analysis:Dunnett’s test if group variances are homogenous
Modified t test is group variances are inhomogenous ($)
BODY WEIGHT (g) OF PREGNANT FEMALES –POST COITUMANDPOST PARTUMPERIODS – MAIN GROUPS – GROUP MEAN DATA
Group(s) |
|
Day of Phase |
|||||
|
0! |
7 |
14 |
20 |
1” |
4 |
|
1 |
(n) Mean SD |
10 262.25 21.09 |
10 294.87 15.77 |
10 334.16 15.23 |
10 424.81 25.24 |
10 314.68 19.39 |
10 315.23 35.00 |
2 |
(n) Mean SD |
10 256.72 13.40 |
10 294.21 15.86 |
10 332.61 19.14 |
10 414.23 33.26 |
10 316.05 20.48 |
10 308.52 20.76 |
3 |
(n) Mean SD |
8 258.81 16.48 |
8 297.51 16.70 |
8 336.34 20.84 |
8 429.21 31.50 |
8 321.90 24.58 |
8 310.40 31.87 |
4 |
(n) Mean SD |
9 356.60 6.76 |
9 288.48 9.48 |
9 323.19 8.28 |
9 402.31 12.52 |
9 311.44 9.82 |
9 300.98 20.89 |
Note: ! = Gestation phase; “ =Post partumphase
* = mean value of group is significantly different from control at p<0.05
** = mean value of group is significantly different from control at p<0.01
Statistical analysis:Dunnett’s test if group variances are homogenous
Modified t test if group variances are inhomogenous ($)
MACROSCOPIC OBSERVATIONS – MAIN GROUP – UNSCHEDULED DEATH – GROUP INCIDENCE
Group: Number in group: |
--Females-- 4 1 |
Kidneys Pelvic dilation |
1 |
Forelimbs Abnormal shape Abnormal consistency |
1 1 |
Hindlimbs Abnormal shape Abnormal consistency |
1 1 |
MACROSCOPIC OBSERVATIONS – MAIN GROUPS – FINAL SACRIFICE – GROUP INCIDENCE
Group: Number in group: |
--Males-- |
--Females-- |
||||||
1 10 |
2 10 |
3 10 |
4 10 |
1 10 |
2 10 |
3 10 |
4 9 |
|
Adrenals Abnormal size |
1 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
Cervical nodes Abnormal colour |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
Kidneys Abnormal area (s) Pelvic dilation |
0 0 |
0 1 |
1 3 |
0 3 |
0 0 |
0 0 |
0 0 |
0 0 |
Liver Abnormal shape Abnormal size |
0 1 |
2 0 |
0 0 |
1 0 |
0 2 |
0 0 |
0 0 |
0 0 |
Ovaries Abnormal size |
|
|
|
|
1 |
0 |
0 |
0 |
Thymus Abnormal area (s) Abnormal colour Abnormal size |
0 0 0 |
1 0 0 |
0 1 0 |
1 0 0 |
0 0 0 |
0 0 1 |
0 0 0 |
0 0 2 |
Uterus Not pregnant Unilateral implantation |
|
|
|
|
0 0 |
0 1 |
2 0 |
0 0 |
Ears Abnormal area (s) |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Whole animal No abnormalities detected |
8 |
6 |
6 |
5 |
7 |
8 |
7 |
7 |
MICROSCOPIC OBSERVATIONS – UNSCHEDULED DEATH – GROUP INCIDENCE
Controls from group (s): 1
Tissues With Diagnoses |
Animal Sex: Dosage group: No. in group: |
--Animals Affected-- --Females-- 4 1 |
Kidneys HYDRONEPHROSIS |
Number examined: |
1 1 |
Lungs EMPHYSEMA INFLAMMATORY CELL FOCI |
Number examined: |
1 1 1 |
Forelimbs ARTHRITIS |
Number examined: |
1 1 |
Hindlimbs ARTHRITIS |
Number examined: |
1 1 |
MICROSCOPIC OBSERVATIONS – FINAL SACRIFICE – GROUP INCIDENCE
Controls from group (s): 1
Tissues With Diagnoses |
|
--Animals Affected-- |
|||||||
Animal Sex: |
--Males-- |
--Females-- |
|||||||
Dosage group: No. in group: |
Ctls 10 |
2 10 |
3 10 |
4 10 |
Ctls 10 |
2 10 |
3 10 |
4 10 |
|
Adrenals ACCESSORY NODULE CORTICAL CELL VACUOLIZATION CYTS/S |
Number examined: |
5 1 1 0 |
0 0 0 0 |
0 0 0 0 |
5 0 1 0 |
5 0 0 0 |
0 0 0 0 |
1 0 0 0 |
5 0 0 1 |
Cervical nodes CONGESTION |
Number examined: |
5 0 |
0 0 |
1 1 |
5 0 |
5 0 |
0 0 |
0 0 |
5 0 |
Heart INFLAMMATORY CELL FOCI |
Number examined: |
5 4 |
0 0 |
0 0 |
5 2 |
5 0 |
0 0 |
0 0 |
5 2 |
Kidneys INFLAMMATORY CELL FOCI NEPHROPATHY HYDRONEPHROSIS |
Number examined: |
5 1 0 0 |
1 0 0 1 |
4 1 2 1 |
5 0 1 2 |
5 0 1 0 |
0 0 0 0 |
0 0 0 0 |
5 0 0 0 |
Liver INFLAMMATORY CELL FOCI HEPATOCYTIC VACUOLATION CLEAR CELL CHANGE EXTRAMEDULLARY HAEMOPOIESIS |
Number examined: |
6 4 1 1 0 |
2 1 0 2 0 |
0 0 0 0 0 |
6 4 0 1 0 |
7 0 0 2 2 |
0 0 0 0 0 |
0 0 0 0 0 |
5 1 0 0 0 |
Lungs AGGREGATION OF ALVEOLAR MACROPHAGES |
Number examined: |
5 1 |
0 0 |
0 0 |
5 2 |
5 4 |
0 0 |
0 0 |
5 4 |
Prostate INFLAMMATORY CELL FOCI |
Number examined: |
5 1 |
0 0 |
0 0 |
5 2 |
|
|
|
|
Testes TUBULAR CELL DEGENERATION |
Number examined: |
5 1 |
0 0 |
0 0 |
5 0 |
|
|
|
|
Thymus ATROPHY CONGESTION |
Number examined |
5 0 0 |
1 0 0 |
1 1 1 |
5 0 0 |
5 0 0 |
1 1 0 |
0 0 0 |
6 1 0 |
Thyroid ECTOPIC THYMIC TISSUE |
Number examined: |
5 1 |
0 0 |
0 0 |
5 2 |
5 0 |
0 0 |
0 0 |
5 0 |
Ears CHRONIC INFLAMMATION |
Number examined: |
1 1 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
Note: Entries flagged with a – (minus) are significantly higher than control at the 0.05 level using the Kolmogorov-Smirnov one-tailed test.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subacute
- Species:
- rabbit
- Quality of whole database:
- Kllimisch 1 - GLP accredited study in accordance with OECD Guideline 422.
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
Repeated dose toxicity via oral route
Male Sprague-Dawley rats were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing, through the mating period and thereafter through the day before necropsy (Days 43 and 44 of study). They were treated for a total of 42 or 43 days. Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
Females were dosed once a day, 7 days a week, for 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum (for approximately 42 days). Dose volumes were adjusted once per week for each animal according to the last recorded bodyweight. During the gestation period, dose volumes were calculated according to individual body weight on Days 0, 7, 14 and 20 post coitum and on Day 1 post partum. Thereafter individual dose volumes remained constant.
Recovery group animals were dosed once a day, 7 days a week, for a minimum of 6 consecutive weeks. No treatment was given during the recovery period.
Each main group comprised 10 male and 10 female rats. Two groups (control and high dose levels) included 5 animals per sex which were sacrificed after 2 weeks of recovery.
One female of the high dose group, receiving 1000 mg/kg bodyweight/day, was killed for humane reasons on Day 3 of the gestation phase.
Marked arthritis of hind limbs and one forelimb, observed at histopathology, could be considered as a factor contributory to the illness status of the animal sacrificed for humane reasons. Therefore, this death was considered to be unrelated to treatment.
No clinical signs of toxicological relevance or signs of neurotoxicity (weekly observations at removal from the cage and in an open arena, alterations in motor activity, grip strength and sensory reaction to stimuli) were observed during the study in males and females. Slight orange staining in the cage tray was observed during the mating phase in some cages of mid- and high dose animals.
No differences in body weight and food consumption were observed in treated animals compared to the control group.
No changes of toxicological significance were recorded at haematological, clinical chemistry investigations or at coagulation tests in animals sacrificed at the end of the study.
No relevant changes were detected at post mortem examination (terminal body weight, organ weights, macroscopic and microscopic examinations) in treated animals, when compared with controls.
Based on the results of the present study, the NOEL (No Observed Effect Level) for general toxicity was considered to be 1000 mg/kg bw/day for males and females.
Justification for classification or non-classification
The results of this study do not trigger classification for repeated dose toxicity in accordance with the CLP Regulation.
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.