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EC number: 603-923-2 | CAS number: 135590-91-9
- 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
Immunotoxicity
Administrative data
Description of key information
Immunotoxicity (EPA OPPTS 870.7800), rat: NOEL immunotoxicity = 591 mg/kg bw/day (females), corresponding to 7500 ppm (highest dose tested)
Key value for chemical safety assessment
Effect on immunotoxicity: via oral route
Link to relevant study records
- Endpoint:
- immunotoxicity: short-term oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 Aug - 06 Oct 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.7800
- Version / remarks:
- adopted Aug 1998
- Deviations:
- yes
- Remarks:
- female rats only, no testing in both sexes as required by the guideline
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Rj:WI (IOPS HAN)
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: R. Janvier, Le Genest St Isle, France
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: 170 – 216 g
- Fasting period before study: no
- Housing: individually, in suspended, stainless steel, wire-mesh cages
- Diet: certified rodent powdered and irradiated diet A04CP1-10 from S.A.F.E. (Scientific Animal Food and Engineering, Augy, France), ad libitum
- Water: filtered and softened water from the municipal water supply, ad libitum
- Acclimation period: 12 days
DETAILS OF FOOD AND WATER QUALITY:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 18 Aug 2010 To: 28 Sep 2010 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substance was incorporated into the diet to provide the required dietary concentrations. The test substance was ground to a fine powder before being incorporated into the diet by dry mixing.
DIET PREPARATION
- Rate of preparation of diet (frequency): There was one preparation for each concentration.
- Storage temperature of food: When not in use, the diet formulations were stored at approximately -18°C. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The homogeneity of test substance in diet was verified before the study for the lowest and highest concentrations to demonstrate adequate formulation procedures. Dietary levels of the test substance were verified for each concentration. The mean value obtained from the homogeneity check was taken as measured concentration.
Homogeneity and concentration results ranged from 93 to 100% of the nominal concentration and were within the in-house target range of 85-115% of the nominal concentration. Stability in rodent diet was analysed in a previous study (refer to study M-136542-01-1-01 under “Repeated dose toxicity”). The stability of the test substance in the dietary formulation was checked under the study conditions. The test substance was found to be stable at 7500 ppm in rodent diet when stored frozen for a period of 32 days, followed by 11 days at room temperature (95% of the nominal concentration). At 500 ppm, the recovery after identical storage conditions was found to be marginally outside the in-house target range (84% instead of 85% of the nominal concentration). Nevertheless, the formulations were considered to be acceptable for the study. - Duration of treatment / exposure:
- 30 days
- Frequency of treatment:
- continuously (via diet)
- Dose / conc.:
- 500 ppm (nominal)
- Remarks:
- equivalent to 40 mg/kg bw/day
- Dose / conc.:
- 2 500 ppm (nominal)
- Remarks:
- equivalent to 199 mg/kg bw/day
- Dose / conc.:
- 7 500 ppm (nominal)
- Remarks:
- equivalent to 591 mg/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Dose levels were chosen on the basis of the results of subacute and subchronic toxicity studies.
- Observations and clinical examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (once daily in weekends or public holidays)
- Cage side observations included: morbidity, mortality, clinical signs
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least weekly
- Detailed physical examinations included: nature, onset, severity, reversibility and duration of clinical signs
BODY WEIGHT: Yes
- Time schedule for examinations: prior to the start of the study (study Day 1), then at weekly intervals throughout the treatment period and before terminal necropsy
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No. The food consumption for each group was determined and the group mean diet consumption (g/day) was calculated per week. The weight of food supplied and of that remaining at the end of the food consumption period was recorded weekly for all animals during the treatment period.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes. The weekly main achieved dosage intake in mg/kg bw/day for each week and for weeks 1 to 4 was calculated. For details please refer to “Any other information in materials and methods incl. tables”.
WATER CONSUMPTION AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
IMMUNOLOGICAL ANALYSIS: Yes
- Time schedule for collection of blood: Blood samples were taken by puncture of the retro-orbital venous plexus 4 days after sheep red blood cell (SRBC) sensitisation. Animals were anesthetised by inhalation of Isoflurane.
- Animals fasted: No
- How many animals: all animals
- Parameters checked: SRBC-specific immunoglobulin M in response to antigen administration. - Sacrifice and pathology:
- SACRIFICE: On study Day 30 all animals from all groups were sacrificed by exsanguination while under deep Isoflurane anesthesia.
GROSS PATHOLOGY: Necropsy included the examination of all major organs, tissues and body cavities. Significant macroscopic abnormalities were recorded but not sampled. At final sacrifice, the following organs were weighed: spleen and thymus.
HISTOPATHOLOGY: No - Cell viabilities:
- SPLEEN: No
THYMUS: No
BONE MARROW: No - Humoral immunity examinations:
- ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA): Yes
- Method: Female rats were treated continuously with the test item, vehicle control or positive control via dietary administration for a period of 28 days. 4 days before necropsy, all animals were immunized with Sheep Red Blood Cell (SRBC) antigen by intravenous injection. At scheduled necropsy, the immunological IgM response following immunization with SRBC was quantified for all animals.
- Dose groups: all dose groups
- No. of animals: all animals - Positive control:
- Cyclophosphamide 3.5 mg/kg bw/day, administered by oral gavage at a constant dosage volume of 5 mL/kg bw.
- Statistics:
- Please refer to the attached document "Statistical analysis_M-402229-01-1.
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related clinical signs were observed throughout the study. An increase in salivation was noted in 4, 3 and 1 animals at 500, 2500 and 7500 ppm, respectively, however, in the absence of a dose-effect relationship, this observation was considered not to be treatment-related. The few other clinical signs observed were considered to be chance findings.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality was observed in any group throughout the study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The mean absolute body weight gain during the first week of treatment at 7500 ppm was 33% lower than in the controls (not statistically significant). Thereafter, mean body weight gain in this group was comparable to controls, however, at the end of the study the absolute body weight gain remained 13% lower compared to the controls (not statistically significant).
- 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 examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- no effects observed
- Description (incidence and severity):
- Please refer to "Specific immunotoxic examinations" for further details.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no relevant changes in organ weights (spleen and thymus) in treated animals when compared to the controls.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related macroscopic changes in treated animals when compared to the controls.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Cell viabilities:
- not examined
- Humoral immunity examinations:
- no effects observed
- Description (incidence and severity):
- The high mean anti-SRBC IgM concentration observed in the control group confirmed the sensitization of the animals. A high inter-individual variability was noted in all groups as is usually observed with SRBC sensitization in the rat. No statistically significant difference was noted in anti-SRBC IgM concentrations up to 7500 ppm. Treatment with the positive control resulted in a markedly lower anti-SRBC IgM concentration when compared to untreated controls, thus demonstrating the functionality of the test system.
- Specific cell-mediated immunity:
- not examined
- Non-specific cell-mediated immunity:
- not examined
- Other functional activity assays:
- not examined
- Other findings:
- not examined
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- immunotox
- Effect level:
- 7 500 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects observed
- Remarks on result:
- other: no immunotoxic potential identified
- Remarks:
- highest dose tested
- Key result
- Critical effects observed:
- no
- Conclusions:
- Treatment of female Wistar rats for 30 days did not impair the immunological IgM resonse following immunization with SRBC antigen up to the highest tested dose of 7500 ppm (corresponding to 591 mg/kg bw/day).
Reference
Table 1: SRBC-specific IgM response
SRBC-specific IgM concentration (u/mL) mean ± standard deviation |
|||||
Dose (ppm) | 0 | 500 | 2500 | 7500 | CPA |
Study Day 30 | 12972 ± 10031 |
13164 ± 9123 |
16798 ± 14767 |
17498 ± 18135 |
1690** ± 1051 |
CPA: Cyclophosphamide, 3.5 mg/kg bw/day; SRBC: Sheep Red Blood Cell ** p < 0.01 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 591 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to assess the endpoint immunotoxicity under Regulation (EC) No. 1907/2006.
Effect on immunotoxicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Effect on immunotoxicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The test item was investigated for immunotoxicity in a subacute oral toxicity study according to EPA OPPTS 870.7800 and in compliance with GLP. The test item was incorporated into the ground diet and administered daily via the diet for a period of 30 days. Groups of 10 female rats per dose received doses of 500, 2500 and 7500 ppm, corresponding to 40, 199 and 591 mg/kg bw/day. Similar constituted groups of animals received the plain diet (negative control) or 3.5 mg/kg bw/day cyclophosphamide (positive control). Four days before necropsy, all animals were immunized with Sheep Red Blood Cell (SRBC) antigen by intravenous injection.
The animals were observed twice daily for mortality and clinical signs; a detailed physical examination was performed prior to and once weekly during the study. In addition, individual body weights and food consumption were recorded once weekly. Just before necropsy, blood samples were collected from each animal for specific anti-SRBC immunoglobulin M (IgM) analysis. After 30 days of treatment, all animals underwent necropsy, gross pathological examination and selected organs were weighed for each animal.
There was no mortality observed during the study period. Clinical signs of toxicity comprised salivation at all dose groups, but a clear dose-response relationship was lacking, thus the findings were considered to be unrelated to treatment. The mean absolute body weight gain of the high dose group animals was reduced during the first week of the study, but comparable to those of control animals thereafter. At the end of the study, the absolute body weight gain remained 13% lower to those of controls. The effect was not statistically significant and therefore considered toxicologically not relevant. At gross pathological examination there were no treatment-related macroscopical changes and no differences in organ weight.
Analysis of the SRBC-induced IgM response revealed no differences of treated animals and control animals up to the highest dose tested. Under the experimental conditions, the test item has no immunotoxic potential. The NOAEL for systemic and the NOEL for immunologic toxicity were 7500 ppm, corresponding to 591 mg/kg bw/day.
Justification for classification or non-classification
The available data on immunotoxicity do not meet the criteria for classification according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for 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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