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EC number: 419-060-8 | CAS number: 79026-02-1 AUFHELLER 2001; ELV 1094
- 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
The no-observed-effect-level (NOEL) of FAT 60253/A in rats was found to be 1000 mg/kg body weight/day.
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:
- 2000
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Hanlbm:WIST (SPF)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd Biotechnology & Animal Breeding Division CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: 6 weeks
- Weight at study initiation: Males: 142 -187 grams (mean 161 grams); Females: 117 -159 grams (mean 143 grams)
- Housing: In groups of five in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 (batch no. 02/00) rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) was available ad libitum. The feed batch was analyzed for contaminants.
- Water (e.g. ad libitum): Community tap-water from Itingen was available ad libitum in water bottles.
- Acclimation period: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light):12 hours fluorescent light/12 hours dark (light period between 06.00 and 18.00), music during the light period. - Route of administration:
- oral: gavage
- Vehicle:
- other: PEG 300
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item formulations were prepared weekly.
FAT 60253/A was weighed into a glass beaker on a tared Mettler balance and the vehicle added. The mixtures were prepared using a magnetic stirrer and stored at room temperature (17-23 °C). Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
VEHICLE
- Lot/batch no. (if required):
a) 405374/1 10200
b) 405371/1 31700 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentration, homogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken after experimental start. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed by RCC Ltd (Environmental Chemistry & Pharmanalytics Division) according to a HPLC method supplied by the Sponsor.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Daily
- Remarks:
- Doses / Concentrations:
0, 50, 200 ad 1000 mg/Kg bw
Basis:
nominal in diet - No. of animals per sex per dose:
- 30 males and 30 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based upon the results of a non-GLP 5-day dose range-finding study (RCC Study Number 777262) in which FAT 60'253/A was administered by gavage to 2 rats per group and sex. Animals showed no overt signs of toxicity.
- Rationale for animal assignment (if not random): Recognized by the international guidelines as the recommended test system. - Positive control:
- No data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed for clinical signs once before commencement of administration; twice daily on days 1-3; as well as once daily on days 4-28 and once daily during days 29-42 (recovery).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. These observations were performed in random sequence once before commencement of administration and once weekly (weeks 1 -3) thereafter.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly during pretest, treatment and recovery and before necropsy, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The food consumption was recorded once during the pretest period and weekly thereafter, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
The following anticoagulants were used during blood collection:
Hematology: EDTA-K2
Methemoglobin: Lithium heparin 30 I.U./ml
Coagulation: Sodium citrate, 3.8 % (1 part anticoagulant to 9 parts blood)
CLINICAL CHEMISTRY: Yes
The following anticoagulant was used during blood collection:
Clinical biochemistry: Lithium heparin 15 I.U./ml;
The following commercial reference controls were used to monitor the performance of the method:
Clinical Biochemistry: Precinorm U (normal range); Precipath U (abnormal range) (Roche Diagnostic GmbH, Mannheim/Germany)
Lyphochek, Level 1 (normal range); Lyphochek, Level 2 (abnormal range)
(Bio-Rad Laboratories, ECS Division, Anaheim, California/USA)
URINALYSIS: Yes - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Slides of all organs and tissues listed in boldface type which were collected at scheduled sacrifice from the animals of control and high-dose groups were examined by a pathologist. - Other examinations:
- None
- Statistics:
- The following statistical methods were used to analyze grip strength, locomotor activity, body weights, organ weights and all ratios, as well as clinical laboratory data :
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Student's T-Test was applied to locomotor activity and grip strength. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
All animals survived until scheduled necropsy.
There were no findings noted during the weekly observations (weeks 1-3).
BODY WEIGHT AND WEIGHT GAIN
The mean body weights and the mean body weight gain of the test item treated animals were similar to those of the control group.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The mean daily food consumption and the relative food consumption of the test item treated groups compared favorably with those of the control animals.
HAEMATOLOGY
After the four-week treatment period, the activated partial thromboplastin times of test itemtreated males were slightly prolonged when compared with the control males. Although the differences noted in males treated with 50 mg/kg/day and 1000 mg/kg/day attained statistical significance (p<0.05), they remained within the 95% confidence limits of the historical control data and were therefore considered to be incidental.
After the two-week recovery period, the ratio of low fluorescence reticulocytes was significantly lower (p<0.01) in males previously treated with 1000 mg/kg/day. This finding was considered to be of no toxicological relevance as similar differences were not evident in the females previously treated with 1000 mg/kg/day.
All other hematology parameters compared favorably after the treatment and recovery periods.
CLINICAL CHEMISTRY
Plasma urea levels were significantly higher (p<0.05) and creatinine levels were significantly lower (p<0.05) in males treated with 50 mg/kg/day, when compared with the controls. Males treated with 200 mg/kg/day or 1000 mg/kg/day were unaffected. The activity of gamma-glutamyltransferase was significantly less (p<0.01) in males treated with 50 mg/kg/day and 200 mg/kg/day when compared with the controls. These differences were considered to be incidental, as males treated with 1000 mg/kg/day were unaffected.
Minor differences noted in various clinical biochemistry parameters after two weeks' recovery were considered to be incidental changes unrelated to the treatment with the test item. All remaining clinical biochemistry parameters compared favorably with those of the controls after four weeks' treatment and two weeks' recovery.
URINALYSIS
There were no test item-related differences noted between control animals and treated animals after four weeks' treatment or two weeks' recovery.
NEUROBEHAVIOUR
There were no findings noted during functional observational battery (week 4).
Grip Strength
The mean hindlimb grip strength of males treated with 200 mg/kg/day or 1000 mg/kg/day was significantly (p<0.05) less than that of control animals. In the absence of similar results in females these findings were considered to be incidental.
Locomotor Activity
The mean locomotor activity was significantly reduced (p<0.05) in males treated with 50 mg/kg/day during the last measurement interval (45-60 minutes) and in males treated with 1000 mg/kg/day during the first measurement interval (0-15 minutes). Conversely, females treated with 1000 mg/kg/day were significantly more active (p<0.05) during the last measurement interval (45-60 minutes). These differences were considered to be incidental. The mean locomotor activity of the remaining groups compared favorably.
ORGAN WEIGHTS
After 4 Weeks
Although the mean absolute liver and kidney weights noted in males treated with 1000 mg/kg/day were significantly higher (p<0.05) than those of the controls, the relative liver and kidney weights of these males were unaffected. The absolute and relative organ weights of the test item-treated females compared favorably with those of the controls.
After 6 Weeks
The absolute and relative organ weights of the test item-treated animals were comparable with those of control animals. - Dose descriptor:
- NOEL
- Effect level:
- ca. 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Critical effects observed:
- no
- Conclusions:
- Based on the results of this study, 1000 mg/kg body weight/day of FAT 60253/A was established as the no-observed-effect-level (NOEL).
- Executive summary:
In this subacute toxicity study, FAT 60253/A was administered daily by oral gavage to SPF bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, PEG 300, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed. Oral administration of FAT 60253/A to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no changes of toxicological relevance in mortality, food consumption, body weight development, clinical signs (daily or weekly), functional observational battery (including grip strength and locomotor activity), parameters of hematology, clinical biochemistry or urinalysis, organ weights, macroscopic and microscopic findings. Based on the results of this study, 1000 mg/kg body weight/day of FAT 60253/A was established as the no-observed-effect-level (NOEL).
Reference
None
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
A key was performed to study the subacute toxicity study of FAT 60253/A. FAT 60253/A was administered daily by oral gavage to SPF bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, PEG 300, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed. Oral administration of FAT 60253/A to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no changes of toxicological relevance in mortality, food consumption, body weight development, clinical signs (daily or weekly), functional observational battery (including grip strength and locomotor activity), parameters of hematology, clinical biochemistry or urinalysis, organ weights, macroscopic and microscopic findings. Based on the results of this study, 1000 mg/kg body weight/day of FAT 60253/A was established as the no-observed-effect-level (NOEL).
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
GLP guideline study
Justification for classification or non-classification
The no-observed-effect-level (NOEL) of FAT 60'253/A in rats was found to be 1000 mg/kg body weight/day.
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