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EC number: 447-920-2 | CAS number: 897393-42-9
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2003-04-28 - 2003-05-26
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- liquid
- Details on test material:
- - Batch: 8191-34
- Purity: 97.8% (expressed as primary amine, % of total)
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): XTJ 568
- Physical state: Clear colourless liquid
- Analytical purity: 97.8%
- Impurities (identity and concentrations): no data
- Purity test date: no data
- Lot/batch No.: 8191-34
- Expiration date of the lot/batch: 01-01-2004
- Stability under test conditions: no data
- Storage condition of test material: at room temperature in the dark, stable under storage conditions
- Other: specific gravity > 0.94 g/cm3
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Wistar Crl:(WI) BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: males: 181-183 g (mean); females: 151-153 g (mean)
- Fasting period before study: not applicable
- Housing: Animals were housed in a controlled environment. Group housing of 5 animals per sex per cage in stainless steel suspended cages with wire mesh floors (55 x 34 x 21.5 cm height). During activity monitoring animals were individually housed overnight in Macrolon plastic cages (type III, height 15 cm) with sterilised sawdust (SAWI, Jelu Werk, Rosenberg, Germany) provided as bedding.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6 - 24.1°C
- Humidity (%): 34-69%
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- Method of administration:
Gavage.
PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 4 hours prior to dosing and were homogenised to a visually acceptable level. Adjustment was made for specific gravity of the test substance. Storage conditions: at ambient temperature. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Accuracy, homogeneity and stability were determined. Analytical method: quantitative analyses were based on the largest peak in the LC-MS chromatogram of XTJ 568.
From the results it was concluded that for formulations of Groups 1-4a relatively high spread was also noted during sample analysis. This spread was however lower than for the procedural recovery samples, particularly at the 200 mg/g level. These results indicate that the analysed concentrations in the formulations do not significantly deviate from 100ù and that the formulations were prepared accurately and homogeneously. Inhomogeneity of test substance formulations in water would be very unlikely since the test substance was found to be mixable with water during NOTOX project 375569. The results of the stability test revealed an apparent 12-14% increase in test substance concentration after 4 hours of storage. This apparent increase falls, however, well within the coefficient of variation of the method. Therefore it can be concluded that test substance formulations were stable during storage for 4 hours. - Duration of treatment / exposure:
- 28 days, 7 days per week
- Frequency of treatment:
- Once daily, approximately the same time each day with a maximum of 4 hours difference between the earliest and latest dose.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Remarks:
- Mid dose
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- High dose
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected on the basis of a 5-day dose range finding study (NOTOX project 375705).
- Rationale for animal assignment (if not random): at random (computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean)
- Dose volume: 5 mL/kg body weight. Actual dose volumes were calculated weekly according to the latest body weight.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily, detailed clinical observations were made in all animals. Once prior to start of treatment and on a weekly basis thereafter (except at the end of week 14), this was also performed outside the home cage in a standard arena. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded:
maximum grade 1: grade 0=absent, grade 1=present
maximum grade 3 or 4: grade 1= slight, grade 2 = moderate, grade 3 = severe, grade 4 = very severe
BODY WEIGHT: Yes
- Time schedule for examinations: On days 1, 8, 15, 22 and 28. Body weights of high dose animals were determined on day 19 prior to sacrifice.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (weekly)
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION : No (subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
Blood samples were collected under iso-flurane anesthesia immediately prior to scheduled post mortem examination, between 7.30 and 9.30 a.m. The animals were fasted overnight (with a maximum of 20 hours) before blood sampling, but water was provided. Animals sacrificed on day 19 were not fasted. Blood samples were drawn from retro-orbital sinus of all rats/sex/group and collected into tubes prepared with EDTA for haematological parameters (0.25 mL), with citrate for clotting tests (1.0 mL) and Li-heparin treated tubes for clinical biochemistry parameters (1.0 mL). The following parameters were determined:
Hematology: erythrocytes count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count, red cell distribution width, total leucocytes count, differential leucocyte count, clotting potential: prothrombin time, partial thromboplastin time
CLINICAL CHEMISTRY: Yes
Parameters checked: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, total, chloride, cholesterol, total, creatinine, glucose, phosphorus, protein, total, protein, albumin, urea, calcium, potassium, sodium.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
During week 4 of treatment, the following tests were performed on all animals:
- hearing ability, pupillary reflex, static righting reflex and grip strength (score 0 = normally/present, score 1 = abnormal/absent)
- motor activity test (recording period: 12 hours during overnight for individual animals, using a computerised monitoring system, Pearson Technical Services, Debenham, Stowmarket, England). - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Necropsy:
All animals surviving to the end of the observation period and all moribund animals were deeply anaesthetised using iso-flurane and subsequently exsanguinated. All animals assigned to the study were necropsied and descriptions of all macroscopic abnormalities recorded. Samples of the following tissues and organs were collected from all animals at necropsy and fixed in a neutral phosphate buffered 4% formaldehyde solution:
aorta, caecum, (clitoral gland), duodenum, (eyes with optic nerve and Harderian gland), (femur including joint), ileum, kidneys, (lacrimal gland, exorbital), lung, infused with formalin, (nasopharynx), ovaries, peyer's patches (jejunum, ileium) if detectable, (preputial gland), rectum, sciatic nerve, (skeletal muscle), spinal cord - cervical, midthoracic, lumbar, sternum with bone marrow, testes, thyroid including parathyroid, trachea, uterus, all gross lesions, adrenal glands, brain (cereellum, mid-brain, cortex), (cervix), colon, epidimydes, (female mammary gland area), heart, jejunum, (larynx), liver, lymph nodes - mandibular, mesenteric, oesophagus, pancreas, pituitary gland, prostate gland, (salivary glands - mandibular, sublingual), (seminal vesicles), (skin), spleen, stomach, thymus, (tongue), urinary bladder, (vagina)
Organ weights:
The following organ weights (and terminal body weight) were recorded from the surviving animals on the scheduled day of necropsy:
adrenal glands, brain, epididymides, heart, kidneys, liver*, spleen, testes, thymus
*: inadvertently not determined from animal no. 1
Histotechnology: All organ and tissue samples were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin.
HISTOPATHOLOGY: Yes
The following slides were examined by a pathologist:
- all tissues and organs collected at the scheduled sacrifice from all animals of the control group, group 3* and 4*: All surviving high dose animals were sacrificed on day 19 for humane reasons. Therefore, group 3 was also examined microscopically
- all tissues and organs from all animals of all dose groups which died spontaneously or were sacrificed in extremis;
- all gross lesions of all animals
Based on potentially treatment-related morphologic changes, the stomach was also examined from all rats of the intermediate dose groups. Tissues mentioned within brackets were not examined as there were no signs of toxicity or target organ involvement. - Statistics:
- - If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one-t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex
- The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution
- The exact Fischer-test was applied to frequency data
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores). Test statistics were calculated on the basis of exact values for means and pooled variances. individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- High dose animals displayed multiple signs starting in the first treatment week, i.e. hunched posture, piloerection, salivation, chromodacryorrhoea, alopecia of the back region (only seen in females) and a lean appearance. Clinical signs observed subsequently in high dose animals included abnormal gait (most males and females), flat gait (one male and one female), transient hypothermia (all males) and swelling of the abdomen (most females and all males). Rales, quick breathing, gasping, ptosis, squeaking and dehydration were occasionally seen among high dose animals. Piloerection was also noted in most or all females dosed at 150 mg/kg/day between weeks 2 and 4. A hunched posture and general swelling of the skin was transiently observed in some mid dose females in weeks 2 and 3. A lean appearance was noted for one mid dose female (no. 34) in the last treatment week, which corresponds to the observed stagnant growth. There were no treatment-related clinical signs in mid dose males.
Lethargy, flat gait, general swelling of the skin and piloerection noted in one female dosed at 50 mg/kg/day (no. 27) were transient, and although a relationship to treatment can not be entirely excluded, these signs were not regarded to be in toxicological terms. Other infrequent findings among animals treated with the test substance included focal erythema or yellow staining of the genital region, scabs and bleeding on the snout (one high dose male no. 16), brown staining of the fur, a broken tail apex, alopecia and/or scales in the shoulder region, chromodacryorrhoea (in one male at 150 mg/kg/day and one female at 50 mg/kg/day) and watery discharge from the eyes. These findings are more frequently noted in rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were considered signs of no toxicological significance. No clinical signs were noted among control animals. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Three males and one female at 1000 mg/kg/day were sacrificed for humane reasons on days 18 and 16, respectively. The remaining high dose animals were killed in extremis on day 19. In addition, one female (no. 40) was found dead on day 7. There was no mortality in other groups.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Markedly reduced weight gain was measured for males and females dosed at 1000 mg/kg/day up to death, attaining statistical significance for males only (p<0.01). The mean weight gain deficit by the end of week 2 was 48% and 40% for high dose males and females, respectively. One of the females (no. 36) showed weight loss (5%) in the first week of treatment. Lower weight gain was also noted for males dosed at 150 mg/kg/day by the end of week 4, resulting in a total weight gain deficit of 13% relative to male controls. In addition, stagnant growth was noted for two females at 150 mg/kg/day (nos. 34 and 35) in week 4, but the mean total weight gain value of this group remained similar to that seen in female controls. Body weights and body weight gain of low dose animals remained in control range over the 4-week study period.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Absolute food consumption of high dose animals was reduced up to death, and the effects were more marked in the first treatment week than in the second. Relative food intake (i.e. after correction for body weight) was reduced in week 1 only. Among other groups, food consumption before or after allowance for body weight was similar to control groups.
- 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):
- High dose animals sacrificed on day 19 showed slightly lower red blood cell counts, haemoglobin values, haematocrit levels and/or mean corpuscular haemoglobin concentration levels. An increased mean corpuscular haemoglobin concentration (HB:HCT ratio) was noted for males dosed at 150 mg/kg/day. This deviation was considered to be incidental in nature and of no toxicological significance since both haemoglobin and haematocrit values were normal. No dose-response relationship was apparent for the statistically significant reduction of red cell distribution width in females dosed at 50 and 150 mg/kg/day. This deviation was also considered to be incidental in nature. Individual increases of neutrophil counts with concurrently reduced lymphocyte counts were noted in female no. 26 (50 mg/kg/day) and female no. 38 (1000 mg/kg/day). This shift in type of white blood cells was considered to be a secondary non-specific response to stress. Animals in a moribund condition often exhibit this pattern.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Pronounced changes noted in all high dose animals sacrificed on day 19 included:
- increased alanine aminotransferase (ALAT) and alkaline phosphatase activity values (ALP)
- increased glucose levels
Less pronounced changes among some or all intercurrently sacrificed animals included increased urea (animal no. 38), potassium (all males and female no. 38), inorganic phosphate (all animals, but within the normal range), chloride (slight in most animals), calcium (males) and cholesterol (all males but within the normal range), and reduced creatinine (animal nos 18, 36 and 39), sodium (all animals, but within the normal range), total protein and albumin (mainly in females). The statistically significant increase of alanine aminotransferase activity in females at 150 mg/kg/day was caused by a slightly high value for female no. 32. This animal also showed an increased alkaline phosphatase activity. Additionally, a high aspartate aminotransferase activity value was noted for female no. 33. There were no statistically significant changes in males at 50 or 150 mg/kg/day. The increased inorganic phosphate levels among females dosed at 50 and 150 mg/kg/day (p<0.05), were considered to be due to slightly lower control values and occurred with no clear dose-related trend. Accordingly, these deviations were considered to be incidental in nature. The higher potassium value of females dosed at 50 mg/kg/day was not accompanied by similar or higher deviations at 150 mg/kg/day and was therefore considered to be of no toxicological significance. No further differences were noted between treated and control animals that were considered to be an effect of treatment. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Functional observations: No changes were observed in hearing ability, pupillary reflex, static righting reflex and grip strength in the animals treated with XTJ 568, when compared to control animals. The variation in motor activity did not indicate a relation with treatment.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Most pronounced organ weight changes noted in high dose animals consisted of:
- increased liver weights and liver to body weight ratios (males and females);
- reduced epididymides weight and epididymides to body weight ratios;
- reduced thymus weight and thymus to body weight ratios (females)
Other changes in organ weights of high dose females were absent when corrected for body weight. Due to low terminal body weights of high dose males, organ to body weight ratios were slightly higher than controls for most remaining organs. Lower absolute liver weights of males dosed at 150 mg/kg/day were absent when corrected for body weight. The changes in absolute testes weights and testes to body weight ratios of males dosed at 50 and 150 mg/kg/day occurred in the absence of a dose-response and considered to be due to lower terminal body weights at 150 mg/kg/day. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment-related findings in high dose animals were noted in the stomach and consisted of:
- Thickening of the limiting ridge (2/5 males) or stomach wall (1/5 males and 1/5 females);
- Crateriform retractions of the glandular mucosa (1/5 males) or forestomach (1/5 males and all females)
- Red discoloration of the limiting ridge (1/5 males), glandular mucosa (1/5 females), or cardia (1/5 females)
- Irregular surface of the forestomach (2/5 males)
- Red foci on the glandular mucosa (1/5 females)
One high dose male (no. 18) did not have macroscopic abnormalities in the stomach. Other findings in these animals consisted of an emaciated appearance (1/5 males), red discoloration of the lungs (2/5 males) and red foci in the caecum (1/5 females). The female found dead on day 7 showed an advanced state of autolysis.
Incidental findings among control and/or treated animals included pelvic dilation of the kidneys, red discoloration of the mandibular lymph nodes, thymus or adrenal glands, red foci on the thymus, enlarged mandibular lymph nodes, fluid in the uterus, reduced size of the liver and spleen (one control female), and liver and pancreas grown together with diaphragm (one female at 150 mg/kg/day). These findings are occasionally seen among rats used in these types of studies. In the absence of a treatment-realted distribution they were considered changes of no toxicological significance. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment-related microscopic observations in high dose animals consisted of:
- moderate to marked squamous epithelial hyperplasia of the forestomach (4/5 males and 5/5 females);
- slight to moderate ulceration of the forestomach (4/5 males and 5/5 females), with associated slight to moderate acute or chronic inflammation;
- increased incidence and severity (slight to moderate) of limiting ridge epithelial hyperplasia (5/5 males and 5/5 females);
- slight to moderate ulceration (2/5 males) of the glandular mucosa of the stomach with associated acute inflammation;
- slight erosion of the glandular mucosa of the stomach (1/5 females);
- slight to moderate cortical lymphoid atrophy of the thymus (4/5 males)
There were no treatment-related microscopic observations in animals dosed at 50 or 150 mg/kg/day. In all groups a number of other histopathological observations were recorded but were considered to be within the normal range and severity of background alterations that may be seen in untreated animals of this age and strain. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Analysis of dose preparations:
Analysis of the accuracy of dose preparations revealed values within the range of 68 -105% of nominal. This variation was considered to be related to the analytical method/test substance properties, and was smaller than the variation seen with the procedural recoveries. Also taking into account the high water solubility of the test substance, formulations in water (Milli-U) were considered to be stable for at least 4 hours and to be prepared homogeneously and accurately at the concentration tested.
Applicant's summary and conclusion
- Conclusions:
- In the study report, a NOAEL of 50 mg/kg bw/day was derived. However, on the basis of the very slight and/or transient body weight effects at 150 mg/kg/day, and the sporadic appearance of clinical signs throughout the study that were in the absence of any histopathological findings, it is considered that 150 mg/kg/day should be the NOAEL for this study.
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.
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