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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
A 28-day oral toxicity study performed according to OECD/EC guideline and GLP principles is available.
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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 07 February 2012 to 06 March 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study has been performed according to OECD and/or EC guidelines and according to GLP principles.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents. Office of Prevention, Pesticides and Toxic Substances (7101), EPA 712-C-00-366, 2000.
- Deviations:
- no
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 6 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20 % of the sex mean.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.7 – 23.3 ºC
- Humidity (%): 41 - 61 %
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12/12
On one day during acclimatization period the lights were turned off for 20 minutes, due to a technical error. Deviation was of a slight and incidental nature, and was therefore considered not to have adversely affected the study outcome.
IN-LIFE DATES: From: 07 February 2012 to 06 March 2012 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 6 hours prior to dosing, and were homogenized to visually acceptable levels. No correction wasmade for the purity of the test substance.
DOSE VOLUME: 5 ml/kg body weight. Actual dose volumes were calculated according to the latest body weight.
On Day 3 and 11 the use of magnetic stirrer was not recorded in the study daybook. The use of the magnetic stirrer is standard in these kinds of studies. Furthermore, the formulation was considered to be homogeneous to visually acceptable levels by the bio-technicians prior to dosing. Based on the low incidence of this deviation and the accepted homogeneity to visually acceptable levels, not recording the use of magnetic stirrer is considered to have no adverse influence on the study outcome. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were conducted on a single occasion during the pretreatment and/or treatment phase, according to a validated method (NOTOX project 497818). Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 6 hours at room temperature under protection from light was also determined (highest and lowest concentration). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110 % of the target concentration for solutions. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Formulations were considered stable if the relative difference before and after storage was maximally 10 %. The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 90 % and 110 %). No test substance was detected in the Group 1 formulation. The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%). Formulations at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 6 hours.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, 7 d/w.
- Remarks:
- Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels are based on results of a10-day dose range finding study with FAT 40854/A (NOTOX project 497845).
- Selection of animals for selected measurements: Recognized by international guidelines as the recommended test system (e.g. EPA, FDA, OECD and EC). - Positive control:
- No.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS:
- Time schedule: At least twice daily.
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: At least once daily from start of treatment onwards, detailed clinical observations were made in all animals immediately after dosing. Once prior to start of treatment and at weekly intervals, this was also performed outside the home cage in a standard arena. The time of onset, grade and duration of any observed signs were recorded.
On Days 8, 15 and 21 the weekly clinical observations (outside the home cage in a standard arena) were performed prior to dosing instead of after dosing. Since no peak period of clinical signs occurred in this study and no clinical signs of toxicity occurred. The time of this weekly observation has no adverse influence on the outcome of the study.
BODY WEIGHT:
- Time schedule for examinations: Weekly.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY:
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: Yes; isoflurane
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: According to test guidelines
CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: Yes; isoflurane
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: According to test guidelines
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION:
- Time schedule for examinations: during week 4 of treatment
- Dose groups that were examined: all animals
- Battery of functions tested: hearing ability, pupillary reflex, static righting reflex and grip strength, motor activity test. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes / No / No data
- All animals were fasated overnight with a maximum of 20 hours prior to planned necropsy, but water was provided. Animals surviving to scheduled necropsy and all moribund animals were deeply anaesthetised and subsequently exsanguinated.
- Dose groups that were examined: all groups
- Tissues/organs checked: According to test guidelines
ORGAN WEIGHTS:
Organs checked according to test guidelines
HISTOPATHOLOGY:
According to test guidelines (+ deviations) - 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 Fisher-test was applied to frequency data.
Motor activity data was subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences followed by the Wilcoxon test to compare the treated groups to the control group. 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) in the summary tables. 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. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY:
No mortality occurred during the study period. No clinical signs of toxicity were noted during the observation period. Red faeces was noted in the highest dose group of males and females. This is considered to have arisen as a result of treatment (red test substance). Incidental findings in single animals that were noted included salivation, scabs and/or a wound. These findings occurred within the range of background findings to be expected for 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.
BODY WEIGHT AND WEIGHT GAIN:
Body weights and body weight gain of treated animals remained in the same range as controls over the study period.
FOOD CONSUMPTION:
Food consumption before or after allowance for body weight was similar between treated and control animals.
HAEMATOLOGY:
No toxicologically relevant changes occurred in haematological parameters of treated rats. Any statistically significant changes at 100 and 300 were considered to be of no toxicological significance as they occurred in the absence of a treatment-related distribution and/or remained within the range considered normal for rats of this age and strain. These findings included: Slightly lower mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) in males at 300 mg/kg and higher neutrophils (%) and lower lymphocytes (%) in females at 300 mg/kg and lower basophils (%) in females at 100 mg/kg. The increases of neutrophil counts with concurrently reduced lymphocyte counts, which were noted in females without a treatment related distribution, could be considered to be a secondary non-specific response to stress and to be of no toxicological significance.
CLINICAL CHEMISTRY:
No toxicologically relevant changes occurred in clinical biochemistry parameters of treated rats. Lower bilirubin levels were noted in males and females at 1000 mg/kg, which remained within the range considered normal for rats of this age and strain. A lower level bilirubin is considered to be not relevant in toxicological terms. Furthermore, any statistically significant changes in females at 100 and 300 mg/kg were considered to be of no toxicological significance as they occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain. These findings included higher level of aspartate aminotransferase (ASAT) and chloride and lower level of inorganic phosphate.
NEUROBEHAVIOUR:
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals. A lower total movement count was noted in females at 1000 mg/kg and a higher total movement count was noted in males at 100 mg/kg. These changes occurred in the absence of a clear dose related distribution, supportive clinical signs and similar results in the opposite sex. Therefore the variation in motor activity is considered to be of no toxicological significance. All groups showed a similar motor activity habituation profile with high activity in the first interval that decreased over the duration of the test period.
ORGAN WEIGHTS:
No toxicologically significant changes were noted in organ weights and organ to body weight ratios. Statistically significant changes were noted in seminal vesicles weights (males 300 mg/kg), relative adrenal weight (males 100 mg/kg) and relative spleen weight (females 300 mg/kg) between treated and control animals. These findings were considered not to be a sign of toxicity as they occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain.
GROSS PATHOLOGY:
Necropsy did not reveal any toxicologically relevant alterations. Reddish discolouration of the glandular mucosa of the stomach was noted in one male at 1000 mg/kg. This finding is considered to be caused by pigment of the test substance, corresponding with the microscopic finding in the stomach. The incidence of other incidental findings among control and treated animals was within the background range of findings that are encountered among rats of this age and strain, and did not show a dose-related incidence trend. These necropsy findings were therefore considered to be of no toxicological relevance, and included scab formation, foci in the stomach, discolouration of the thymus and fluid in the uterus.
HISTOPATHOLOGY: NON-NEOPLASTIC
In the kidney a dose-dependent increased incidence and severity was noted in hyaline droplets (up to moderate) in males at 300 and 1000 mg/kg/day. In this study the occurrence of cortical hyaline droplets was accompanied by a slightly increased incidence and severity of corticomedullary tubular basophilia in males at 300 and 1000 mg/kg/day compared to control. (Group 1: 3/5 grade 1, Group 2: 1/5 grade 1, Group 3: 1/5 grade 1 and 1/5 grade 2, and Group 4: 1/5 grade 1 and 2/5 grade 2). Red/brown pigment was noted in the mucosa of the stomach (minimal to slight) in half of the animals of Group 4. In addition red/brown pigment was noted in the Peyer’s patches (minimal) in half of the animals of Group 4. The nature and severity of these microscopic findings were not considered to be toxicologically relevant and not adverse. All other microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other:
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Critical effects observed:
- no
- Conclusions:
- From the results presented in this report a No Observed Adverse Effect Level (NOAEL) for FAT 41043/A of at least 1000 mg/kg was established.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The study has a Klimisch code 1.
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
28-d oral toxicity
Wistar rats (5/sex/dose) were treated with FAT 41043/A for 28 consecutive days by daily oral gavage at a dose level of 0, 100, 300 or 1000 mg/kg bw. No toxicologically significant changes were noted in any of the parameters investigated in this study (i.e. clinical signs, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). From the results presented in this report a NOAEL for FAT 41043/A of at least 1000 mg/kg bw was established.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
only reliable study available performed according to guideline
Justification for classification or non-classification
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.
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