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EC number: 255-392-8 | CAS number: 41484-35-9
- 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
In a 90-day feeding study in rats adaptive changes in liver weights and minimal hepatocyte hypertrophy were the only relevant effects reported. The NOAEL was considered to be 138 mg/kg bw/day for males and 140 mg/kg bw/day for fermales.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1983-1984
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted May 12, 1981
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Tif: RAIf
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Animal Production Stein, CIBA-GEIGY Ltd.,4332 Stein, Switzerland
- Age at study initiation: 4 weeks
- Weight at study initiation: males: 96 - 101 g, females: 95 - 102 g
- Housing: 5 per cage
- Diet: standard diet Nafag No. 890 Tox, ad libitum
- Water: tap water ad libitum
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 16 - 20
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: July 16, 1983 To: November 4, 1983 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): The test substance was weighed on a calibrated Mettler balance. The pulverised food was then homogeneously mixed with the appropriate concentrations of the compound and 30% water was added before pelleting to ensure the necessary pellet quality. The pellets were subsequently airdried. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prior to the initiation of the study, pretest feed samples were analysed for concentration of the test material. The same was undertaken periodically with the food batches applied during the test. These analysis were carried out in the Central Analytical Laboratories of CIBA-GEIGY LTD., Basle/Switzerland.
- Duration of treatment / exposure:
- 93 - 103 days
- Frequency of treatment:
- daily
- Dose / conc.:
- 60 ppm
- Remarks:
- Corresponding to 4.4 mg/kg bw in males and 4.5 mg/kg bw in females.
- Dose / conc.:
- 200 ppm
- Remarks:
- Corresponding to 12.5 mg/kg bw in males and 13 mg/kg bw in females.
- Dose / conc.:
- 600 ppm
- Remarks:
- Corresponding to 39 mg/kg bw in males and 40 mg/kg bw in females.
- Dose / conc.:
- 2 000 ppm
- Remarks:
- Corresponding to 138 mg/kg bw in males and 140 mg/kg bw in females.
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, plain diet
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily (a.m. and p.m. on working days)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly (midweek)
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
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
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly during the first month, monthly thereafter
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before (day -4) and towards the end (day 87) of the treatment period
- Dose groups that were examined: control animals and in treated animals of the highest dose level
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No
- How many animals: all animals
- Parameters checked: Erythrocytes (RBC), Mean Corpuscular Volume (MCV), Hematocrit (PCV), Hemoglobin (Hb), Mean Corpuscular Hemoglobin (MCH), Thrombocytes (PLT) (Platelet Count), Leucocytes (WBC) Total Count, Leucocytes (WBC) Differential Count, Prothrombin Time (PT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: Glucose, Blood Urea Nitrogen (BUN), Total Bilirubin, Creatinine, Total Protein, Albumin, Globulins, A/G Ratio, Sodium (Na+), Potassium (K+), Chloride (Cl-), Calcium (Ca++), Phosphorus Inorganic, Asp. Aminotransferase ASAT (GOT), Ala. Aminotransferase ALAT (GPT), Alkaline Phosphatase (AP), Gamma-Glutamyl Transpeptidase (GGT), Cholesterol
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: Hearing test:
- Time schedule for examinations: before (day -4) and towards the end (day 87) of the treatment period
- Dose groups that were examined: control animals and in treated animals of the highest dose level - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Besides the weight of the exsanguinated body the following organs were weighed: brain, heart, liver, kidneys, adrenals, thymus, gonads, spleen, thyroid
- The following organs and tissues were preserved in neutral 10% formalin:
skin, mammary area, spleen, mesenteric lymph node, axillary lymph node, sternum with bone marrow, femur with joint, skeletal muscle, trachea, lung, heart, aorta, submandibular salivary gland, liver, pancreas, oesophagus, stomach, small intestine, large intestine, kidney, urinary bladder, prostate, seminal vesicle, testis, epididymis, uterus, ovary, pituitary gland, adrenal gland, thyroid with parathyroid gland, thymus, peripheral nerve, brain, spinal cord, eye with optic nerve, orbital gland, extraorbital lacrimal gland, organs and tissues showing macroscopical changes
HISTOPATHOLOGY: Yes
- After the fixation organ samples from each control and test rat were taken, embedded in paraplast, sectioned at 3-5 micron, stained with haematoxylin and eosin and subjected to microscopic examination. - Statistics:
- For each time point and parameter a uni-variate statistical analysis was conducted. Due to the routine manner of the analysis system, parameter free methods were applied. Each treated group was compared to the control group in respect of dispersion and displacement. In addition a trend test was applied considering all groups.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical symptoms and no signs of local and/or systemic toxicity were observed.
- Mortality:
- no mortality observed
- Description (incidence):
- No death occurred during the 3 months test period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- The mean body weight gain of all treated male and female groups was similar to that of the respective control groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- The mean food consumption of all treated male and female groups was similar to that of the respective control groups. Specific food consumption in relation to body weight - usually referred to as food conversion ratio - in treated animals was similar to that of the respective control groups.
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- The mean water consumption of all treated male and female groups was similar to that of the respective control groups.
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- Ophthalmic inspections performed before (day -4) and towards the end (day 87) of the application period revealed no evidence of a reaction to the treatment.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- The findings in the hematological investigation were unremarkable and considered as incidental in nature and not related to the treatment with the test substance.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- The values of treated rats were unremarkable and comparable to those of the control group. Parameters achieving a level of statistical significance in their difference from control values were considered to have arisen fortuitously.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean organ weights and ratios are presented in the attached summary tables. Both absolute and relative liver weight showed a dose dependent increase reaching the level of statistical significance in treated male groups 3, 4 and 5 (200, 600 and 2000 ppm) and in treated female group 5 (2000 ppm). Additional statistically significant differences in organ weights, as indicated by asterisks in the attached mean tables, between treated and control groups were noted. Since no systematic pattern emerged, except a trend to higher kidney and testis weights in males and thyroid weight in males and females at higher dosages - which corresponds to the higher weight of exsanguinated body in these groups - these differences were attributed to spontaneous variation rather than to the treatment.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No abnormal substance related findings were observed.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Minimal hypertrophy of hepatocytes was present in the centrilobular region of the liver in all treated males of group 5 (2000 ppm), in 6 males of group 4 (600 ppm) and in 3 females of group 5 (2000 ppm). Only 19 liver samples were examined in female group 5 (liver of animal no 197 was missing). All other findings in control and treated animals are considered to be incidental in nature.
- Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- Hearing test: Hearing tests performed before (day -4) and towards the end (day 87) of the application period revealed no treatment related effects on the auditory perception.
- Dose descriptor:
- NOEL
- Effect level:
- 60 ppm
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Dose descriptor:
- NOAEL
- Effect level:
- >= 140 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- female
- Basis for effect level:
- other: highest dose tested
- Dose descriptor:
- NOAEL
- Effect level:
- >= 138 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male
- Basis for effect level:
- other: highest dose tested
- Critical effects observed:
- not specified
- Executive summary:
In a 90 day repeated dose toxicity study by the oral route following OECD guideline 408, a total of 40 RAIf rats (20 each sex) were fed with the test material at dosages of 60, 200, 600 and 2000 ppm for three months. According to analytical results the calculated mean daily intake was 4.4-138 mg/kg bw (male) and 4.5-140 mg/kg bw (female). No death occurred. The body weight gain, the food and water consumption of males and females were similar to the control. No clinical symptoms and no signs of local and/or systemic toxicity were observed and no effects in eye and hearing tests were noted. Haematology and blood chemistry showed no effect associated to the test substance. The organ weight analysis showed a dose-dependent increase of the liver weight at and above 200 ppm in males and at 2000 ppm in females. The only histopathological finding was a minimal hypertrophy in the centrilobular region of the liver in males at and above 600 ppm and females at 2000 ppm. It can be inferred from the observations made during the above study that a "no observable effect level" (NOEL) for the test material when offered to rats continuously in their feed over a period of 3 months is 60 ppm, corresponding to a mean daily intake of 4.4 mg/kg body weight for males and 4.5 mg/kg bw for females. Because the observed changes were considered adaptive in nature, the NOAEL was set 138 mg/kg body weight (highest dose tested)
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 138 mg/kg bw/day
- Study duration:
- subchronic
- 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 valid subchronic study according to OECD 408 is available. In this study a total of 200 RAI (SPF) rats (20 males and 20 females per dose group) were used. The test article was administered daily in the diet for 3 months at doses of 0, 60, 200, 600 and 2000 ppm (= mg/kg feed). The results of the study are summarized as follows:
According to the analytical results the calculated mean daily intake of the test substance was approximately 4.4, 12.5, 39 and 138 mg/kg body weight in males and 4.5, 13, 40 and 140 mg/kg body weight in females. The mean body weight gain, mean food consumption, specific food consumption and water consumption of all treated male and female groups was similar to that of the respective control groups. No death occurred during the course of the study and no clinical symptoms and no signs of local and/or systemic toxicity were observed. Ophthalmic inspections and hearing examinations performed before and towards the end of the application period revealed no evidence of a reaction to the treatment. The findings in the hematological investigation were unremarkable. Occasional intergroup differences were considered incidental in nature and not related to the treatment with the test substance. The values found in the clinical chemistry of treated rats were unremarkable and comparable to those of the control group. Parameters achieving a level of statistical significance in their difference from control values were considered to have arisen fortuitously. Both absolute and relative liver weight showed a dose dependent increase reaching the level of statistical significance in treated male groups 3, 4 and 5 (200, 600 and 2000 ppm) and in treated female group 5 (2000 ppm). Apart from minimal hypertrophy in the centrilobular region of the liver (20/20 males and 3/19 females at 2000 ppm, and 6/20 males at 600 ppm), no macroscopical or microscopical findings were present that could be considered to be due to the administration of the test compound.
In conclusion it can be stated that the increase in liver weight is not correlated with an impaired liver function since no effects were found in the biochemical analysis. So this effect is considered to be adaptive and the NOAEL corresponds to the highest dose used which is 140 mg/kg bw/day for fermales and 138 mg/kg bw/day for males.
Similar adaptive responses were reported in three additional studies performed by IBT in rats and dogs, supporting the above discussed findings. However, since IBT was found to have generated fake data especially for studies with repeated exposure, the reliability of these study reports is questionable. Although they seem to support the results obtained in a reliable study, it was decided to disregard these IBT studies and not to consider them as supporting information.
Justification for classification or non-classification
Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008
The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the present data, classification for repeated dose oral toxicity is not warranted under Regulation (EC) No.1272/2008.
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