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EC number: 269-505-3 | CAS number: 68259-02-9
- 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
The "no-observed-adverse-effect level" was considered to be 50 mg/kg bw/day for male and female rats when administered orally by gavage for a period of 28 days.
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:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- For a detailed read across justification please refer to chapter 13.
- Reason / purpose for cross-reference:
- read-across source
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wolferstrasse 4 4414 Fuellinsdorf/Switzerland
- Weight at study initiation: Males: 170.30 - 195.27 g; Females: 115.82 - 161.15 g
- Housing: Individually in Makrolon type-3 cages with autoclaved standard softwood bedding ('Lignocel', Schill AG, CH-4132 Muttenz).
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: From 19-May-1994 to 25-May-1994 under laboratory conditions, after veterinary examination. Only animals without any visual signs of illness were used for the study.
ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 25 °C
- Humidity: 40 - 70 %
- Air changes: 10 - 15 air changes per hour
- Photoperiod: 12 hours artificial fluorescent light. 12 hours dark, music during the light period. - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- bi-distilled water
- Details on oral exposure:
- Dose levels
Group 1 (control): 0 mg/kg bw/day
Group 2: 50 mg/kg bw/day
Group 3: 200 mg/kg bw/day
Group 4: 1000 mg/kg bw/day
Test Article Preparation:
The test article was weighed into a glass beaker on a tared Mettler PM 480 balance and the vehicle was added. The mixture (w/v) was prepared using a homogenizer. Homogeneity of the test article in the vehicle was maintained during treatment using a magnetic stirrer.
Vehicle Bi-distilled water Frequency of preparation Daily prior to each application Chemical analysis of dose preparation
Concentration, homogeneity and stability of the test article/vehicle mixtures were determined during acclimatization. Further samples for analysis were taken during week 3 of the test and subsequently analyzed. The analyses were performed in the Analytical Laboratories of RCC Umweltchemie AG, according to a method which was supplied by the sponsor. - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Not available
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, 7 days per week for a total of 28 days.
- Remarks:
- Doses / Concentrations:
0, 50, 200 and 1000 mg/kg per day
Basis:
no data - No. of animals per sex per dose:
- Groups 1 and 4: 10 males; 10 females
groups 2 and 3: 5 males and 5 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Based upon data from acute oral toxicity study (RCC Project 371777) and a 5-day dose-range finding study (RCC Project 371834) in which FAT 45'168 / A
was administered orally by gavage to rats. - Positive control:
- Not available
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS & MORTALITY:
Observations for mortality/viability and clinical signs of toxicity were recorded once daily.
BODY WEIGHT: The body weight of each animal was recorded on the same days as the food consumption using the same recording system. Additionally, terminal body weights were recorded at necropsy.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The food consumption was recorded once during the acclimatization period and weekly thereafter using an on-line electronic recording system consisting of a
Mettler PM 4800 balance connected to the RCC computer.
OPHTHALMOSCOPIC EXAMINATION: Yes
Dates: at 4 weeks: 20-0UN-1994
at 6 weeks: 04-JUL-1994
A description of any abnormality was recorded. 10 - 90 minutes after the application of a mydriatic solution (Dispersa AG, CH-8442 Hettlingen) the cornea, lens, anterior chamber, vitreous body and ocular fundus of both eyes were examined under dimmed light using a Heine BETA 200 Ophthalmoscope (Eisenhut Vet. AG, CH-4123 Allschwil).
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes - Sacrifice and pathology:
- NECROPSY
after 4 weeks - 23-JUN-1994
after 6 weeks - 07-JUL-1994
All animals were weighed and necropsied and descriptions of all macroscopic abnormalities were recorded. Prior to necropsy, the animals were fasted for
approximately 18 hours, but free access to water was provided. Necropsies were performed by experienced prosectors supervised by an experienced veterinary pathologist. At the end of the treatment or recovery period the animals designated according to the necropsy schedule were anesthetized by
intraperitoneal injection of NARCOREN (Rhone Merieux GmbH, D-88471 Laupheim) at a dose of 2.0 ml/kg body weight (equivalent to 320 mg sodium pentobarbitone/kg body weight), weighed and sacrificed by exsanguination. Samples of the following tissues and organs were collected from all animals at
necropsy and fixed in phosphate buffered neutral 4 % formaldehyde solution:
Adrenals; aorta; bone (sternum, femur); bone marrow (sternum, femur); brain; cecum; colon; duodenum; epididymides; esophagus; eyes with optic nerve and Harderian gland; femur including joint; heart; ileum; jejunum; kidneys; larynx; lacrimal gland, exorbital; liver; lung infused with formalin; lymph nodes,
mandibular, mesenteric; mammary gland area; nasal cavity; ovaries; pancreas; pituitary gland; prostate gland; rectum; salivary gland, (mandibular, sublingual); seminal vesicles; sciatic nerve; skeletal muscle; skin; spinal cord, (cervical, midthoracic, lumbar); spleen; stomach; testes; thymus; thyroid incl.
parathyroid gland; tongue; trachea; urinary bladder infused with formalin; uterus; vagina and gross lesions.
ABSOLUTE AND RELATIVE ORGAN WEIGHTS
The following organ weights were recorded on the scheduled dates of necropsy: Adrenals, brain, heart, kidneys, liver, ovaries, pituitary, spleen, testes,
thyroid including parathyroid gland. The organ to terminal body weight ratios as well as the organ to brain weight ratios determined:
The determination of the terminal body weight was performed immediately prior to necropsy using an on-line electronic recording system consisting of a Mettler PM 4000 balance connected to a computer system.
HISTOTECHNIQUE
All organ and tissue samples, as defined under Histopathology were processed, embedded, cut at an approximate thickness of 4 micrometers, and stained with hematoxylin and eosin.
HISTOPATHOLOGY
Slides of adrenals, heart, kidneys, liver, lungs, spleen, stomach and testes collected at terminal sacrifice from the animals of the control and high-dose
groups were examined by a pathologist. The same applied to all gross lesions from all rats and to all animals which died spontaneously or have to terminated in extremis. All abnormalities were described and included in the report. - Other examinations:
- Not available
- Statistics:
- The following statistical methods were used to analyze the body weights, food consumption, organ weights, all ratios and clinical laboratory data :
When 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 between the treated groups and the control groups for each sex.
The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
The Fisher's exact test was applied to the ophthalmoscopy data. - 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 examined
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- not examined
- 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:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No animal died during the course of study.
During the treatment period blue coloring of the feces was observed in animals of all treated groups.
There were no other treatment-related findings.
BODY WEIGHT AND WEIGHT GAIN
There were no effects on the mean body weight or body weight development in any dose group.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Absolute and/or relative food consumption were increased in males and females of group 4 (1000 mg/kg bw/day) during the third and fourth week of treatment.
No test article related changes were observed in any other group.
OPHTHALMOSCOPIC EXAMINATION
There were no treatment-related ophthalmoscopic findings.
HAEMATOLOGY
The assessment of hematological data indicated the following effects in rats of groups 3 (200 mg/kg bw/day) and/or 4 (1000 mg/kg bw/day) at termination of the treatment:
- Slightly increased reticulocyte count (relative/absolute) in both sexes of group 4 with a tendency towards higher values in group 3, slightly increased HFR and slightly decreased LFR reticulocyte fluorescence ratio in males of group 4, and markedly increased methemoglobin (MET-HB) concentration in both sexes of group 4 with a slight increase observed in group 3. In addition, an increased incidence of polychromatophilia was noted in both sexes of group 4.
The findings were considered to be treatment-related and suggest methemoglobinemia with an increase in hemopoietic activity as indicated by the increase
in reticulocytes. At termination of the treatment-free recovery period these findings were found to be reversed and comparable to those of the controls.
CLINICAL CHEMISTRY
In the assessment of clinical biochemistry data the following effects were recorded in rats of groups 3 (200 mg/kg bw/day) and/or 4 at termination of the
treatment:
- Slightly increased urea level in females (group 4), slightly increased creatinine level in both males and females (group 4), markedly increased uric acid and total bilirubin level in both males and females (group 4) and slightly increased in both males and females (group 3), slightly increased total cholesterol level in both males and females (group 4), slightly decreased triglyceride level in both males and females (group 4), slightly increased phosphorus level in females (group 4), marginally increased chloride level in females (group 4), slightly increased albumin and total protein level in both males and females (group 4), and slightly increased albumin to globulin ratio in males (group 4). In addition, a dark blue discoloration of the plasma was observed in all animals
of group 4 and a light blue discoloration in all animals of group 3. These findings were considered to be test article related. At termination of the treatment-free recovery period most of these findings were found to be reversed and comparable to those of the controls, except for a slightly increased uric acid and total bilirubin level in both sexes and a slightly increased phosphorus level in females of group 4. Moreover, a light blue discoloration of the plasma was yet to be noted in all animals of this group.
URINALYSIS
Urinalysis data indicated no changes which could be considered of toxicological significance at termination of the treatment. The only alterations noted were a deep brown to brown urine discoloration in both sexes of group 4 (1000 mg/kg bw/day) and a deep yellow urine pigmentation in three males and five females of group 3 (200 mg/kg bw/day). Also noted was a slight increase in the urine pH in females of group 4, slight increase in urine protein in both males and females of group 4 and marked increase in urine bilirubin (scores) in both males and females of group 4 with a slight increase in group 3. The discoloration was an expected effect of the test article, whereas the increase in urine bilirubin suggests a false positive reaction due to interference of the test article or metabolites thereof with the reagent test-strip reaction. This was also supported by the fact that "Ictotest" used to confirm positive bilirubin reaction was found to be negative in all cases nor was this latter observation supported by any underlying morphological findings which would suggest disturbed bilirubin metabolism, liver dysfunction or biliary obstruction. At termination of the treatment-free recovery period these findings were generally reversed and comparable to those of the controls, except for a slight increase in urine bilirubin and a yellow grey urine discoloration in both sexes of group 4.
ORGAN WEIGHTS
In comparison with the control group, no treatment-related effects on the organ weights or organ weight ratios were noted.
GROSS PATHOLOGY
At necropsy general and kidney discoloration (bluish) was observed in animals of group 3 and 4 (200, 1000 mg/kg bw/day). This was reversible after cessation of treatment. At histopathological examination slightly increased extramedullar haematopoesis was observed in 2 males and 1 female of group 4 (1000 mg/kg bw/day) at the end of the treatment period and also in 1 male each of group 1 and 4 (0, 1000 mg/kg bw/day) after recovery.
No other treatment-related macroscopic or microscopic findings were noted. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 200 mg/kg bw/day (nominal)
- System:
- haematopoietic
- Organ:
- blood
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- The "no-observed-adverse-effect level" of FAT 45168/A is 50 mg/kg bw/day for male and female rats when administered orally by gavage for a period of 28 days.
- Executive summary:
In this subacute toxicity study, FAT 45168/A was administered daily by gavage to SPF-bred Wistar rats of both sexes at dose levels of 0, 50, 200 and 1000 mg/kg bw/day for a period of 28 days. After termination of the treatment period half of the animals of the control group and of the high dose group were observed for a further 14-day treatment free recovery period.
The only toxicologically significant observation during the in-life phase was an increase in food intake noted for both sexes of group 4 (1000 mg/kg bw/day) during the third and fourth week of treatment. At clinical laboratory investigations a number of slight to marked effects on biochemical, hematological and urinary parameters were noted for rats of group 4 (1000 mg/kg bw/day) and - in some cases - also of group 3 (200 mg/kg bw/day). In conclusion, these findings reflect methemoglobinemia with an increase in hemopoietic activity and with the corresponding histopathological findings of slightly increased splenic extramedullar hematopoiesis.
Based upon the results obtained in this study, the "no-observed-adverse-effect level" of FAT 45168/A is 50 mg/kg bw/day for male and female rats when administered orally by gavage for a period of 28 days.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- High quality GLP study
- System:
- haematopoietic
- Organ:
- blood
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
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
A sub-acute toxicity study, using the FAT
45'168 / A (source chemical which is used for read across) was
administered daily by gavage to SPF-bred Wistar rats of both sexes at
dose levels of 0, 50, 200 and 1000 mg/kg bw/day for a period of 28 days.
After termination of the treatment period half of the animals of the
control group and of the high dose group were observed for a further
14-day treatment free recovery period. The only toxicologically
significant observation during the in-life phase was an increase in food
intake noted for both sexes of group 4 (1000 mg/kg bw/day) during the
third and fourth week of treatment. At clinical laboratory
investigations a number of slight to marked effects on biochemical,
hematological and urinary parameters were noted for rats of group 4
(1000 mg/kg bw/day) and - in some cases - also of group 3 (200 mg/kg
bw/day). In conclusion, these findings reflect methemoglobinemia with an
increase in hemopoetic activity and with the corresponding
histopathological findings of slightly increased splenic extramedullar
hematopoiesis. Based upon the results obtained in this study, the
"no-observed-adverse-effect level" of FAT 45'168/A is 50 mg/kg bw/day
for male and female rats when administered orally by gavage for a period
of 28 days. The test for repeated dose inhalation has been waived for
the reason that the test substance has very low vapour pressure, so the
potential for the generation of inhalable forms is low, also the use of
this substance will not result in aerosols, particles or droplets of an
inhalable size, so exposure to humans via the inhalation route will be
unlikely to occur. Furthermore, in the 28-days repeated dose study via
oral gavage administration does not exacerbate systemic toxicity effects
which suggest bioavailability is low, thereby there is low toxicity
potential. This intrinsic property/toxicity potential can be
extrapolated to repeated inhalation route administration. To fill in the
gap for repeated dose (dermal) study the data from several other
relevant study were observed and analysis of our substance does not
indicate any harm upon oral exposure and neither the chemical structure
of the substance nor any toxicokinetic results raise any concern about
the toxic behavior of the substance upon dermal absorption, we will not
perform any test on this endpoint.
Justification for classification or non-classification
The "no-observed-adverse-effect level" of Read across substance FAT 45'168 / A is 50 mg/kg body weight for male and female rats when administered orally by gavage for a period of 28 days. Hence classified as STOT RE 2 as per CLP guideline.
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