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EC number: 619-020-1 | CAS number: 94361-06-5
- 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
- Oral: No adverse effects on the immune system observed, female, mice, sub-acute, EPA 870.7800, Wasil 2012
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:
- supporting study
- Study period:
- 3 Jan 2012 to 13 Feb 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.7800
- Version / remarks:
- 1998
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- mouse
- Strain:
- CD-1
- Remarks:
- Crl:CD1(ICR)
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: were approximately 7 weeks old
- Weight at randomization: 20.5 to 26.7 g
- Housing: housed individually in clean, stainless steel, wire mesh cages suspended above cage board
- Diet: Certified Rodent LabDiet® 5002 (meal), ad libitum
- Water: Reverse osmosis-treated (on-site) drinking water, ad libitum
- Acclimation period: 13-day
ENVIRONMENTAL CONDITIONS
- Temperature (°C): mean daily temperature ranged from 21.3 to 21.4 °C
- Humidity (%): mean daily relative humidity ranged from 34.8% to 38.9%
- Air changes (per hr): minimum of 10
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 28 Day
- Frequency of treatment:
- continuously
- Dose / conc.:
- 10 ppm
- Remarks:
- Group 2. Dietary equivalent to 2.1 mg/kg of body weight/day.
- Dose / conc.:
- 30 ppm
- Remarks:
- Group 3. Dietary equivalent to 7.0 mg/kg of body weight/day.
- Dose / conc.:
- 100 ppm
- Remarks:
- Group 4. Dietary equivalent to 23.0 mg/kg of body weight/day.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Positive control:
- Cyclophosphamide (CPS) at a concentration of 5 mg/mL: Group 5.
- Dose descriptor:
- NOAEL
- Remarks:
- humoral immune response (AFC Assay)
- Effect level:
- 100 ppm
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- 30 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 100 ppm
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Conclusions:
- The administration of the test item in the diet for 28 consecutive days to female Crl:CD1(ICR) mice at dose levels of 10, 30, and 100 ppm resulted in a no-observed-effect-level (NOEL) for the AFC assay (humoral immune response) of 100 ppm (equivalent to 23.0 mg/kg of body weight/day), the highest dose level evaluated. The no-observed-adverse-effect level (NOAEL) for this study, based on the increased liver weights observed in the 100 ppm dose group, was 30 ppm (equivalent to 7.0 mg/kg of body weight/day).
- Executive summary:
The test substance, was offered ad libitum in the diet for 28 consecutive days to female Crl:CD1(ICR) mice in Groups 2, 3, and 4 at dietary concentrations of 10, 30, and 100 ppm, respectively. The concurrent control group (Group 1) and the positive control group (Group 5) were offered the basal diet on a comparable regimen to the test item-treated groups. All mice (Groups 1-5) were immunized with an intravenous injection of sheep red blood cells (sRBC) on study day 24. Mice in the positive control group (Group 5) were administered the positive control substance, cyclophosphamide (CPS), via intraperitoneal injection (50 mg/kg/day) once daily for 4 consecutive days (study days 24 through 27). Each group consisted of 10 mice/group. All animals were euthanized on study day 28.
All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed once daily for all animals. Detailed physical examinations were performed approximately weekly and on the day of the scheduled necropsy. Individual body weights and food consumption were recorded approximately twice weekly. Complete necropsies were conducted on all animals. The liver, mesenteric lymph node, Peyer’s patches, spleen, and thymus were collected at the scheduled necropsy, and the liver, spleen, and thymus were weighed. Spleens were placed in Earle’s Balanced Salt Solution (EBSS)/HEPES buffer, spleen cell suspensions were prepared, spleen cell counts were performed, and the number of specific IgM antibody-forming cells directed towards the sRBC antigen were determined to measure the humoral immune response using the splenic Antibody-Forming Cell (AFC) assay.
All animals survived to the scheduled necropsy. There were no test item-related clinical observations, macroscopic findings, or effects on body weights or food consumption. There were no test item-related effects on spleen cell numbers and the test item did not significantly suppress the humoral immune response when evaluated as either specific activity (AFC/106 spleen cells) or as total activity (AFC/spleen) of splenic IgM to the T-cell dependent antigen sRBC. Adverse, test item-related higher liver weights were noted in the 100 ppm group. For the positive control group, CPS, statistically significantly lower spleen and thymus weights, spleen cell numbers, specific activity, and total spleen activity of IgM antibody-forming cells were noted when compared to the vehicle control group. These effects were consistent with the known immunosuppressant effects of CPS and validated the functionality of the assay.
Based upon the results of this study, the test item administered ad libitum in the diet for 28 consecutive days to female Crl:CD1(ICR) mice at dose levels of 10, 30, and 100 ppm resulted in a no-observed-effect-level (NOEL) for the AFC assay (humoral immune response) of 100 ppm (equivalent to 23.0 mg/kg of body weight/day), the highest dose level evaluated. The no-observed-adverse-effect level (NOAEL) for this study, based on the increased liver weights observed in the 100 ppm dose group, was 30 ppm (equivalent to 7.0 mg/kg of body weight/day).
Reference
Analyses of Diet
Prior to dosing, test diet homogeneity was established at 8 and 120 ppm based on the protocol-specified acceptability limits (90% to 110% of the target concentration and had a relative standard deviation [RSD] ≤ 5%). In addition, the 8 and 120 ppm test diet admix formulations were found to be stable for up to 15 days of room temperature storage (≥90% of initial value). The analyzed diet admix formulations that were administered to the animals were found to contain 97.4% to 105% of the test substance, which were within the protocol-specified range (90% to 110% of target concentration and had an RSD ≤ 5%), except for the 10 ppm test diets prepared on 2 days which had RSD values of 9.1% and 5.9%, respectively, which were above the protocol-specified acceptability limits. However, these test diets were used for dose administration. Administration of the out-of-specification 10 ppm dietary admix formulations did not impact the integrity or interpretation of the study as the values were within the SOP range (RSD ≤ 10%). The test substance was not detected in the basal diet that was administered to the vehicle and positive control groups (Groups 1 and 5, respectively).
Survival
All animals survived to the scheduled necropsy.
Clinical Observations
There were no test item-related clinical observations. All clinical findings in the test item-treated groups were noted with similar incidence in the control group, were limited to single animals, were not noted in a dose-related manner, and/or were common findings for laboratory mice of this age and strain.
Body weights
Body weights were unaffected by administration of the test item in the diet. Mean body weight tended to be numerically lower than the vehicle control group values in the 100 ppm group after study day 10 of the study, but a clear relationship to treatment with statistical significance was not apparent. Occasional statistically significant differences in body weight gains were probably due to biological variability and were not considered related to test substance administration due to lack of a clear dose-response trend and/or the changes were in a direction not considered toxicologically relevant.
Food and Test Substance Consumption
Food consumption was unaffected by the test item administration. There were no statistically significant differences when the control and test substance-treated groups were compared.
Macroscopic examination
There were no test item-related macroscopic findings. All macroscopic findings noted were considered to be spontaneous and/or incidental in nature and unrelated to test substance administration.
Organ weights
Test item-related higher liver weights were noted in the 100 ppm group. Higher mean absolute, relative (to terminal body weight), and adjusted mean liver weights were noted in the 100 ppm group when compared to the vehicle control group, and the adjusted values were statistically significant. Mean adjusted liver weights in the 100 ppm group were 20.5% higher than the vehicle control group. Based on the magnitude of the increase in liver weights and the lack of histopathological evaluation, this change was considered adverse. There were no treatment-related effects of the test item on spleen or thymus weights. In the positive control group (CPS), absolute and adjusted mean spleen and thymus weights were statistically significantly lower than the vehicle control group values.
AFC Assay
There were no test item-related effects on spleen cell numbers, specific activity, or total spleen activity at any dietary concentration evaluated. As expected, statistically significantly lower spleen cell numbers, specific activity, and total spleen activity were noted in the positive control (CPS) group when compared to the vehicle control group, which validated the functionality of the assay.
Natural Killer Cell (NKC) Assay
Based on the lack of indications for immunotoxicity, there was no need to conduct an NKC assay with the test item.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 7 mg/kg bw/day
- Study duration:
- subacute
- Species:
- mouse
- Quality of whole database:
- Study performed under GLP and in accordance with EPA 870.7800 Guideline
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 substance was administered in the diet for 28 consecutive days to female mice at dose levels of 0, 10, 30 and 100 ppm (equivalent to 0, 2.1, 7.0 and 23.0 mg/kg bw/day) resulted in and increased absolute and relative liver weight at 100 ppm and higher. No effects on the immune system were found. The NOEL for the AFC assay (humoral immune response) of 100 ppm (equivalent to 23.0 mg/kg bw/day), the highest dose level evaluated. The no-observed-adverse-effect level (NOAEL) for this study, based on the increased liver weights observed in the 100 ppm dose group, was 30 ppm (equivalent to 7.0 mg/kg bw/day)
Justification for classification or non-classification
Based on the available information, classification for effects on the immune system upon repeated exposure is not warranted according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC)1272/2008.
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