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Diss Factsheets
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EC number: - | CAS number: -
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
Materials and methods
- Objective of study:
- absorption
- toxicokinetics
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.7485 (Metabolism and Pharmacokinetics)
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Test material form:
- solid: particulate/powder
- Details on test material:
- Purity: 93.6%
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories International, Inc., Raleigh, North Carolina, U.S.A.
- Age at study initiation: 9 - 11 weeks
- Weight at study initiation: 299 - 366 g
- Fasting period before study: Animals for the oral and intravenous administration experiments were fasted (approximately 18 ± 2 hours) before dosing with test substance. Animals for the repeat dose 14-day oral administration experiment were not fasted before dosing with the test substance. Food was returned approximately 2 hours post dose.
- Housing: During the pretest period, animals were group housed (non-cannulated) or housed individually (cannulated) in solid bottom caging with Bed-O-Cob® and Nestlets. For the in-life phase, animals were housed individually in solid-bottom caging with Bed-O-Cob® and Nestlets.
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002 ad libitum, except when fasted
- Water: tap water ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26ºC
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- other: single oral gavage, intravenous, or 14-day repeated oral gavage
- Vehicle:
- other: oral gavage doses were prepared with 0.1% Tween 80 with 0.5% methylcellulose; intravenous dose was prepared with 10% dimethyl sulfoxide, 10% glycerol formal, and 2.5% tween 80 in 40% hydroxypropyl-β-cyclodextrine solution
- Details on exposure:
- PREPARATION OF TEST SUBSTANCE FORMULATION:
- Solvent used:
Oral Gavage doses were prepared with 0.1% Tween 80 in 0.5% methylcellulose
Intravenous dose was prepared with 10% dimethyl sulfoxide, 10% glycerol formal, and 2.5% tween 80 in 40% hydroxypropyl-β-cyclodextrine solution
- Preparation frequency: once
- Preparation details: The test item was mixed with 0.5% methylcellulose with 0.1% Tween 80 for oral gavage administration or 10% dimethyl sulfoxide, 10% glycerol formal, and 2.5% tween 80 in 40% hydroxypropyl-β-cyclodextrine solution for intravenous administration. The formulation for oral administration was a homogenous suspension and the intravenous formulation was visibly observed to be a clear solution. Furthermore, the intravenous dose was sterile filtered through a 0.22 μm filter.
- Adjusted for purity: no - Duration and frequency of treatment / exposure:
- Single oral gavage administration
14-day repeated oral gavage administration
Single intravenous administration
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Single oral gavage: 50 (Group 1) or 1000 mg/kg bw (Group 2)
14-day repeated oral gavage: 50 mg/kg bw (Group 4)
Single intravenous: 5 mg/kg bw (Group 3)
- No. of animals per sex per dose / concentration:
- 4 per dose level
- Control animals:
- no
- Details on study design:
- - Dose selection rationale: The high dose was set at 1000 mg/kg bw, which is the maximum dose recommended per OECD Guideline 417. The low dose was set at 50 mg/kg bw, which was selected to bracket the two lowest doses in the 2-week dose range-finding toxicity study by oral gavage in rats. For the intravenous administration experiment, a dose of 5 mg/kg bw was chosen, which is 1/10 of the low dose for the single dose oral gavage experiment. For the repeated dose 14-day oral gavage experiment, the dose was set to 50 mg/kg bw, which is equal to the low dose for the single oral gavage experiment.
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood from tail vein
- Time and frequency of sampling:
Oral gavage: 0, 15 and 30 min, as well as at 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours
Intravenous administration: 0, 2, 5, 15, and 30 min, as well as at 1, 2, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours
- Other: Blood was processed into plasma, which was stored frozen at ≤-10°C until it was analysed
- From how many animals: samples pooled across the 4 animals
- Method type(s) for identification: HPLC-MS
- Limits of detection and quantification: The LOD and LOQ for the test item were 0.75 and 2.5 ng/mL, respectively. - Statistics:
- Group data were represented as a mean ± SD as appropriate. Tables and appendices presented in the report were computer generated and values were rounded appropriately for inclusion in the report. Consequently, the application of manual calculation to report values may have, in some instances, yielded a minor variation. These occurrences should not be construed as adversely affecting the integrity or interpretation of the data.
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- In summary, the pharmacokinetics of the test item showed that 1) it was rapidly absorbed and eliminated; 2) bioavailability decreased from 30.2% to 5.58%, indicating a saturation in absorption as the dose increased from 50 mg/kg bw to 1000 mg/kg bw; and 3) it did not accumulate following 14-day repeated oral gavage dosing.
Toxicokinetic parametersopen allclose all
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 5660 (±1490) ng/mL single low dose oral
- Test no.:
- #2
- Toxicokinetic parameters:
- Cmax: 11500 (±1500) ng/mL single high dose oral
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 0.5 (±0.0) hours single low dose oral
- Test no.:
- #2
- Toxicokinetic parameters:
- Tmax: 0.88 (±0.25) hours single high dose oral
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 10400 (±1900) hr x ng/mL single low dose oral
- Test no.:
- #2
- Toxicokinetic parameters:
- AUC: 38400 (±7200) hr x ng/mL single high dose oral
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 2.0 (±0.4)hours single low dose oral
- Test no.:
- #2
- Toxicokinetic parameters:
- half-life 1st: 5.6 (±1.8) hours single high dose oral
- Test no.:
- #3
- Toxicokinetic parameters:
- Cmax: 6140 (±670) ng/mL intravenous administration
- Test no.:
- #3
- Toxicokinetic parameters:
- Tmax: 0.046 (±0.025) hours intravenous administration
- Test no.:
- #3
- Toxicokinetic parameters:
- AUC: 3430 (±300) hr x ng/mL intravenous administration
- Test no.:
- #3
- Toxicokinetic parameters:
- half-life 1st: 2.0 (±0.7) hours intravenous administration
- Test no.:
- #4
- Toxicokinetic parameters:
- Cmax: 6080 (±1580) ng/mL 14-day repeated dose oral gavage
- Test no.:
- #4
- Toxicokinetic parameters:
- Tmax: 0.51 (±0.02) hours 14-day repeated dose oral gavage
- Test no.:
- #4
- Toxicokinetic parameters:
- AUC: 10100 (±2200) hr x ng/mL 14-day repeated dose oral gavage
- Test no.:
- #4
- Toxicokinetic parameters:
- half-life 1st: 4.0 (±2.0) hours 14-day repeated dose oral gavage
Metabolite characterisation studies
- Metabolites identified:
- no
Any other information on results incl. tables
Based on the dose administration data, all animals received the targeted dose for each treatment group. There were no clinical signs observed in any test group.
For the intravenous administration experiment, mean peak plasma concentration (Cmax) was 6140 (±670) ng/mL and the Tmax value was observed at 0.046 (±0.025) hours. The mean terminal elimination half-life (T1/2) value was 2.0 (±0.7) hours with an area-under-the-curve (AUC) value of 3430 (±300) hr x ng/mL. The volume of distribution (V) and clearance (CL) values were 4270 (±1610) mL/kg and 1460 (±140) mL/hour/kg.
For the single dose oral gavage experiment, Cmax at the low and high dose were 5660 (±1490) and 11500 (±1500) ng/mL, respectively. Absorption was rapid with mean Tmax values of 0.50 (±0.0) and 0.88 (±0.25) hours at the low and high dose, respectively. The T1/2 values were 2.0 (±0.4) and 5.6 (±1.8) hours at the low and high dose, respectively. The AUC for the low and high dose were 10,400 (±1900) and 38400 (±7200) hr x ng/mL, respectively. Oral bioavailability decreased from 30.2 (±6.2) % to 5.58 (±1.15) % as the dose increased from 50 mg/kg bw to 1000 mg/kg bw, indicating a saturation in absorption.
For the 14-day repeated dose oral gavage experiment, the Cmax and Tmax values were 6,080 (±1580) ng/mL and 0.51 (±0.02) hours, respectively. Elimination was rapid with a T1/2 value of 4.0 (±2.0) hours. The AUC value was 10100 (±2200) hr x ng/mL, which is slightly less than 10400 (±1,900) hr x ng/mL, the value obtained after the single oral gavage dose. This indicates that the test item did not accumulate following 14-day repeated oral gavage dosing.
Applicant's summary and conclusion
- Conclusions:
- Not likely to accumulate following multiple dosing.
The pharmacokinetics of the test item showed that it was rapidly absorbed and eliminated. Bioavailability of the test item decreased from 30.2% to 5.58%, indicating a saturation in absorption as the dose increased from 50 mg/kg bw to 1000 mg/kg bw. The test item did not accumulate following 14-day repeated oral gavage dosing. - Executive summary:
The toxicokinetics of the test item was studied in male Sprague-Dawley rats. Experiments were performed to understand plasma kinetics following single oral gavage, intravenous, or 14-day repeated oral gavage administration. Four male rats were administered the test item at 50 or 1000 mg/kg bw by single oral gavage. Another four male rats were administered the test item at 50 mg/kg bw daily by gavage for 14 days. Following the last administered dose, blood was collected via the tail vein at 15 and 30 min, as well as at 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours.
Based on the dose administration data, all animals received the targeted dose for each treatment group. There were no clinical signs observed in any tested group.
For the intravenous administration experiment, mean peak plasma concentration (Cmax) was 6,140 (±670) ng/mL and the Tmax value was observed at 0.046 (±0.025) hours. The mean terminal elimination half-life (T1/2) value was 2.0 (±0.7) hours with an area-under-the-curve (AUC) value of 3,430 (±300) hr x ng/mL. The volume of distribution (V) and clearance (CL) values were 4,270 (±1,610) mL/kg and 1,460 (±140) mL/hour/kg.
For the single dose oral gavage experiment, Cmax at the low and high dose were 5660 (±1490) and 11500 (±1500) ng/mL, respectively. Absorption was rapid with mean Tmax values of 0.50 (±0.0) and 0.88 (±0.25) hours at the low and high dose, respectively. The T1/2 values were 2.0 (±0.4) and 5.6 (±1.8) hours at the low and high dose, respectively. The AUC for the low and high dose were 10400 (±1900) and 38400 (±7200) hr x ng/mL, respectively. Oral bioavailability decreased from 30.2 (±6.2) % to 5.58 (±1.15) % as the dose increased from 50 mg/kg bw to 1000 mg/kg bw, indicating a saturation in absorption.
For the 14-day repeated dose oral gavage experiment, the Cmax and Tmax values were 6080 (±1580) ng/mL and 0.51 (±0.02) hours, respectively. Elimination was rapid with a T1/2 value of 4.0 (±2.0) hours. The AUC value was 10100 (±2200) hr x ng/mL, which is slightly less than 10400 (±1900) hr x ng/mL, the value obtained after the single oral gavage dose. This indicates that the test item did not accumulate following 14-day repeated oral gavage dosing.
In summary, the pharmacokinetics of the test item showed that 1) it was rapidly absorbed and eliminated; 2) bioavailability of the test item decreased from 30.2% to 5.58%, indicating a saturation in absorption as the dose increased from 50 mg/kg bw to 1000 mg/kg bw; and 3) it did not accumulate following 14-day repeated oral gavage dosing.
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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