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EC number: 213-551-9 | CAS number: 976-56-7
- 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
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1983
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- absorption
- distribution
- excretion
- Principles of method if other than guideline:
- - Principle of test: Different groups of male rats were treated with 14C-labeled test material followed by analysis of excrements, blood, organs and carcass to determine absorption, distribution and excretion of the test material.
- Short description of test conditions:
A single oral dose of the radiolabeled test material was given to 4 different exposure groups. Animal killing was performed at various time (3 h, 8h, 24 h, 72 h, 168 h) after treatment in test animal group 1 for examination of whole body sections. In test animal group 2 blood samples were taken at specified times for measurements of the substance / substance metabolite concentration. Animals of group 3 were examined for the rate of excretion in feces and urine by sampling at various time. Animals of test group 4 recieved 1/20 of the substance dose of test group 3 (otherwise the objection was identical wih group 3).
- Parameters analysed / observed: Determination of radioactivity in urine, faeces, blood, organs (liver, kidneys, testicles), tissue samples (muscle, fat) - GLP compliance:
- yes
- Specific details on test material used for the study:
- RADIOLABELLING INFORMATION
- Radiochemical purity: > 99 %
- Specific activity: 59.388 µCi/mg
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
Test solution preparation with the vehicle
The solid test substance was dissolved in the vehicle;
Test solution A (for animal test groups 1 and 2) with 2605,1 µg test substance/g solution and 152,24 µCi/g;
Test solution B (for animal test group 3) with 2596,1 µg test substance/g solution and 153,41 µCi/g
Test solution C (for animal test group 4) with 150.1 µg test substance/g solution and 8,834 µCi/g
FORM AS APPLIED IN THE TEST (if different from that of starting material): Solution - Radiolabelling:
- yes
- Remarks:
- 14C-radiolabelling
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga GmbH, 8741 Sulzfeld/Germany
- Weight at study initiation: 172-182 g
- Housing: For 7 days before administration of the test substance and during the experimental phase the control and test rats were housed separately in metabolism cages.
- Individual metabolism cages: Yes
- Diet: Dr. Rupprecht Schott Nachf. GmbH + Co., Hamburg/Germany, Art.-No. 253, ca. 22 g/day (except the day before administration of test substance, only 8 g)
- Water: tap water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-1
- Humidity (%): 55+/-5
- Photoperiod: 12 hrs dark / 12 hrs light - Route of administration:
- oral: gavage
- Vehicle:
- other: A mixture of equal parts by weight of 1,2-dihydroxypropane and tap water.
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The radioactive solution as well as the non-labelled solution were prepared shortly before administration to the test animals. Calculated amounts of 14-C-labelled or non-labelled test material were weighed in the glass vessels of an Ultrasonic homogeniser and dissolved in the defined amounts of the test vehicle at 30 °C within 30 minutes.
- Duration and frequency of treatment / exposure:
- Single oral exposure
- Dose / conc.:
- 10.88 mg/kg bw (total dose)
- Remarks:
- Test group 1 (Distribution)
- Dose / conc.:
- 10.71 mg/kg bw (total dose)
- Remarks:
- Test group 2 (Absoprtion)
- Dose / conc.:
- 10.67 mg/kg bw (total dose)
- Remarks:
- Test group 3 (Excretion)
- Dose / conc.:
- 0.53 mg/kg bw (total dose)
- Remarks:
- Test group 4 (Excretion)
- No. of animals per sex per dose / concentration:
- Test group 1 (Distribution): 5 test and 2 control animals
Test group 2 (Absorption): 6 test and 2 control animals
Test group 3/4 (Excretion): 6 low dose and 6 high dose test animals, 2 control animals - Control animals:
- yes
- Details on dosing and sampling:
- TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine, faeces, blood, organs (liver, kidneys, testicles), tissue samples (muscle, fat)
- Time and frequency of sampling:
Tissue/organ samples after 168 h (test group 3 and 4)
Urine, faeces: Collection during the entire experimental period (test group 3 and 4)
urine: 0-3, 3-6, 6-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168 h after treatment; feces: 0-6, 6-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168 h after treatment
Blood after 168 h ( test group 3 and 4) and after 0.25, 0.5, 1, 2, 4, 6, 12, 24, 48, 72, 120 and 168 h (test group 2) - Type:
- absorption
- Results:
- Only small amounts were absorbed from the gastrointestinal tracts into the blood, reaching a maximum within the first and second hour after administration.
- Type:
- distribution
- Results:
- Absorbed radioactivity was concentrated significantly but only temporarily in the livers, virtually completely eliminated during period of study.
- Type:
- excretion
- Results:
- Within 168 h after oral administration an average of 87.6 % and 86.3 % (high dose and low dose, respectively) of the dose was excreted, mainly via the feces (85.4 % and 84.9 %). Further amounts of radioactivity were exhaled.
- Details on absorption:
- The absorption of the test substance from the gastrointestinal tract of the rat has a maximum between the first and second hour after oral administration. In this period, the average equivalent concentration amounted to about 0.78 µg test substance per g blood. The subsequent decrease of the average equivalent concentration of the test substance in the blood of the rats is clearly shown by the values at 48 h and 168 h after oral administration of 0.029 and 0.005 µg, resp., test substance per g blood (for details see table 1 "Any other information on results").
- Details on distribution in tissues:
- Autoradiograms showed that the substance was absorbed only in small portions from the gastrointestinal tracts and was concentrated significantly only in the liver of the test rats and only temporarily. These radioactivities and the clearly lower concentrations over the remaining organs and tissues of the test animals werealmost completely eliminated during the progress of experiment.
The gastrointestinal tracts of the rats killed at 168 h contained on average about 0.01% of the dose. As a consequence of the enormous elimination of the C-labelled test substance and/or its metabolites in faeces and urine, the results show that only small amounts of radioactivity were found in the blood, the organs, tissue samples and in the residual carcass. At the time of sacrifice, the blood of the rats contained an average of less than 0.01 % of the dose and about 0.06 % and 0.1 % were present in the residual carcasses of high dose and low dose animals, respectively. The blood, organs and tissue samples taken at the time of sacrifice and the residual carcass of the rats from the high dose group contained average equivalent concentrations from 3.7 (testicles) to 29.5 ng test substance (liver) per g, whereas the blood, organs, tissue samples and the residual carcass of the rats from the low dose animals contained only average equivalent concentrations from 0.3 (blood) to 2.7 ng test substance (liver) per g (for details see table 2 and table 3 "Any other information on results"). - Details on excretion:
- An average of 85.4 % and 84.9 % of the given radioactivities were eliminated in the faeces by rats from the high dose and low dose, respectively, within 168 h after oral administration of the 14C-labelled test substance. In the same interval, an average of 2.2 % and 1.4 % of the radioactivity amounts orally administered in form of the 14C-labelled test substance were found in the urine of the rats. According to these results, the rats, excreted, an average of 87.6 % (high dose) and 86.3 % (low dose) within 168 h after oral administration. As pre-tests showed, the test rats exhaled further amounts of radioactivity.
- Conclusions:
- No bioaccumulation potential can be concluded based on the study results. The orally given test material and its possible metabolites are retained for only a limited time in male rats and are preferentially excreted in the feces, but also via the kidneys and by respiration.
- Executive summary:
Absorption, distribution and elimination of the test substance by male rats was quantitatively investigated by radiotracer techniques under GLP-conditions. Simultaneously the residues
of the test substance and/or its metabolites in blood, different organs and tissue samples and in the residual carcass of the test animals
were determined radioanalytically. For that purpose the total of 29 male Sprague-Dawley rats was divided
into control and test groups. After an adaptive phase of 7 days, each rat of the test group 1-4 was given a single oral dose of about I0.9, 10.7, 10.7 or 0.53 mg of C-labelled test substance per kg body weight. The rats of the control groups were each given an average oral dose of about 10.5 mg of non-labelled
test item per kg of body weight and produced biological material samples which were used for the determination of blanc values for
radioactivity assays of feaces, urine, organs, blood etc..
During the study period (168 h) all urine and faeces from the rats of the test groups 3/4 as well as from two rats of the control
group were collected quantitatively during certain periods of time. At the end of the test, the anaesthetized rats were killed by bleeding to death. The blood was collected separately
from each animal and as for liver, kidneys, testicles, muscle and fat samples, the residual carcass and all faeces and urine samples the radioactivity content measured. From the animals of test group 2 and the respective control group, blood samples were obtained at specific times after administration by puncture of the ophthalmic venous plexus. The blood samples were also assayed for radioactivity measurement.
From the radioactivities of the biological samples, the excretion rates in feces and urine of radioactivity and the relative or equivalent concentrations of the test item in
blood, in different organs, tissue samples and in the residual carcass were calculated. The rats of test group 1 were killed at 3, 8, 24, 72 and l68 h after oral administration of the C-labelled test substance, and two animals of the control group were killed at 8 and 72 h after oral administration of the unlabelled test substance. Sagittal whole body sections of the eye-kidney, the suprarenal gland, the thyroid gland and the median plan were made. The whole body sections, after freeze drying, were placed on photographic films in order to examine the distribution of radioactivity over the different body planes. The investigation showed that the rats from test groups 3 and 4 eliminated on average 87.6 % (85.4 % in feces and 2.2 % in urine) and 86.3 % (84.9 % in feces and 1.4 % in urine) respectively, of the oral dose of test substance. Further, not yet quantified, portions of the applied radioactivity were exhialed by the rats.
Also, at 168 h after the oral administration of the C-labelled test item only small amounts of radioactivity were found in the dead bodies of the rats from test groups 3and 4.
At the time of killing the animals, the radioactivity in the blood the organs liver/kidneys/testicles, the gastrointestinal tracts and the residual carcass of the rats from test groups 3 and 4 amounted to < 0.01, < 0.04, 0.01 and 0.06 % and 0.0l, <0.05, 0.01 and 0.10 % respectively of the dose.
The absorption of radioactivity given orally in form of the C-labelled test substance from the gastrointestinal tracts of the rats reached a maximum within the first and second hour after administration (test group 2). Radioactivity given perorally in form of C-labeled test item was absorbed in only small portions from the gastrointestinal tracts and were concentrated significantly but only temporarily in the livers - as compared with all other organs and tissues of the test rats of group 1. However, such radioactivity and that distributed clearly and evenly in lower concentrations over the residual carcass of the rats was virtually completely eliminated during period of study.
Reference
Table 1: Radioactivities, the average relative and equivalent concentrations of the orally administered test substance in the blood of rats after different time points.
|
Test substance |
|
Radioactivity of blood [nCi/g] at time after administration [h] |
||||||||||||
|
Radioactivity |
Dose |
0.25 |
0.5 |
1 |
2 |
4 |
6 |
12 |
24 |
48 |
72 |
120 |
168 |
|
|
[µCi] |
[µCi/g bw] |
[mg/kg bw] |
|
|
|
|
|
|
|
|
|
|
|
|
Average |
114.12 |
0.6228 |
10.711 |
17.39 |
36.52 |
45.67 |
41.09 |
17.06 |
12.67 |
5.988 |
4.066 |
1.714 |
0.9623 |
0.4406 |
0.2786 |
Standard deviation |
3.4 |
0.018 |
0.32 |
9.84 |
23.55 |
32.79 |
25.70 |
3.6 |
3.62 |
1.54 |
1.42 |
1.33 |
0.53 |
0.14 |
0.07 |
Relative standard deviation (%) |
3.0 |
3.0 |
3.0 |
56.6 |
64.5 |
71.8 |
62.5 |
21.3 |
28.6 |
25.7 |
34.8 |
77.6 |
54.8 |
32.0 |
27.9 |
Average relative concentration |
|
|
|
27.780 |
58.339 |
72.955 |
65.636 |
27.249 |
20.233 |
9.565 |
6.496 |
2.738 |
1.537 |
0.704 |
0.4455 |
Average equivalent concentration |
|
|
|
0.2976 |
0.6249 |
0.7814 |
0.7030 |
0.2919 |
0.2167 |
0.1025 |
0.0696 |
0.0293 |
0.0165 |
0.0075 |
0.0048 |
Relative concentration = average measured radioactivity per g test material/administered radioactivity per g body weight at time of intubation
Equivalent concentration = Relative concentration * dose administered (mg/g bw) * 1000 [µg/g test material]
Table 2: Excretion of radioactivity (%) in urine and feces by rats given 14C-labeled test material by intubation.
|
|
|
Average excreted radioactivity amounts [%(sd)] |
||||||||
Group |
Number of animals |
Route of excretion |
0-3 h |
3-6 h |
6-24 h |
24-48 h |
48-72 h |
72-96 h |
96-120 h |
120-144 h |
144-168 h |
high dose |
6 |
urine |
0.31 (0.26) |
0.26 (0.08) |
1.41 (1.46) |
0.17 (0.11) |
0.04 (0.02) |
0.01 (0.01) |
0.01 |
0.01 |
0.01 |
feces |
0.03 (0.03) |
76.99 (5.12) |
7.95 (3.65) |
0.36 (0.24) |
0.07 (0.01) |
0.03 (<0.01) |
0.01 (<0.01) |
0.01 |
|||
low dose |
6 |
urine |
0.17 (0.09) |
0.24 (0.1) |
0.72 (0.12) |
0.18 (0.10) |
0.04 (0.01) |
0.03 (0.01) |
0.03 (0.01) |
0.02 |
<0.01 |
feces |
|
67.95 (6.13) |
16.05 (4.39) |
0.74 (0.43) |
0.12 (0.05) |
0.04 (0.02) |
0.02 (0.01) |
0.02 (0.01) |
Table 3. Summary of the average radioactivity amounts in %, of the average relative (P) and equivalent concentrations (C) after 168 h.
tissue | radioactivity amount (%) | average relative concentration (P) | equivalent concentration (C) (ng/g) | |||
group | high dose | low dose | high dose | low dose | high dose | low dose |
urine | 2.2 | 1.4 | ||||
feces | 85.39 | 84.94 | ||||
GI tract | 0.01 | 0.01 | ||||
blood | < 0.01 | < 0.01 | 0.53 | 0.66 | 4.6 | 0.3 |
liver | 0.02 | 0.03 | 3.39 | 6.29 | 29.5 | 2.7 |
kidneys | < 0.01 | < 0.01 | 1.29 | 2.07 | 11.3 | 0.9 |
testicles | < 0.01 | < 0.01 | 0.43 | 0.88 | 3.7 | 0.4 |
muscle | < 0.01 | < 0.01 | 0.63 | 1.16 | 5.5 | 0.5 |
fat | < 0.01 | 0.01 | 2.38 | 3.95 | 20.7 | 1.7 |
residual carcass | 0.06 | 0.1 | 0.72 | 1.34 | 6.2 | 0.6 |
recovered radioactivity | 87.68 | 86.49 |
Relative concentration P = average measured radioactivity per g test material/administered radioactivity per g body weight at time of intubation
Equivalent concentration C = Relative concentration * dose administered (mg/g bw) * 1000 [µg/g test material]
Description of key information
Key value for chemical safety assessment
Additional information
Assessment of the toxicokinetic behavior of test substance
The test substance (molecular weight of 356 g/mol is a white solid powder (Siemens, 2014) with a log Pow of 2.9 (BASF, 2014) and a water solubility of 14 mg/L (BASF, 2014). The vapor pressure was determined to be 1.73E-6 Pa at 20°C (Ciba-Geigy, 1976). The toxicokinetic properties of a structurally related compound were examined in an ADE study performed with rats, investigating the absorption, distribution and excretion characteristics (NATEC, 1983). These results are used in addition to toxicity data and physico-chemical parameters to assess the properties of the test article in a read across approach (see Annex of the CSR for read-across justification).
Absorption/Distribution
Oral application
The results of the available toxicokinetics study showed, that 14C-labeled test material of the structurally related compound given orally is absorbed only in small portions from the gastrointestinal tracts into the blood, reaching a maximum within the first and second hour after administration. Absorbed radioactivity was concentrated significantly but only temporarily in the livers. The radioactivity in the liver and the clearly lower concentrations in the remaining organs and tissues of the test animals were almost completely eliminated during the progress of experiment. The available toxicokinetic study could show that within 168 hours after oral administration an average of 87.6% and 86.3% (high dose and low dose, respectively) of the dose was excreted, mainly via the feces (85.4% and 84.9%). Further amounts of radioactivity were exhaled.
Dermal application
No toxicokinetic data is available for the dermal route. Dermal uptake is favored for chemicals with a molecular weight < 100 g/mol, while for chemicals with a molecular weight > 500 g/mol, dermal uptake is not favored (ECHA GD 7c,2008). In addition, Log P values between 1 and 4 favor dermal absorption. These data indicate that absorption through the skin might occur.
Exposure by inhalation
No experimental data from acute or repeated dose inhalation toxicity studies are available, which could provide information about the systemic distribution of the test substance after inhalation. The test article is a powder with a low vapor pressure. Only 3.8% of particles were determined with a size of < 10µm, therefore only small amounts will reach the alveolar region. Absorption is likely to occur due to the log Pow of 2.9, which favors absorption directly across the respiratory tract epithelium by passive diffusion.
Metabolism
Using the OECD toolbox 3.1, the liver metabolism simulator predicted hydroxylation of the alkyl side chain. Furthermore, metabolites were proposed where dealkylation of the phosphate group took place, leading to the cleavage products ethanol and acetaldehyde. Studies on genotoxicity (Ames-Test, HPRT, MNT) gave no indications of a reactivity of test substance or its metabolites under the test conditions (i.e. no increased mutagenicity and cytotoxicity in treatments with metabolic activation).
Excretion
The available toxicokinetic study with the structurally related compound could show that within 168 hours after oral administration an average of 87.6% and 86.3% (high dose and low dose, respectively) of the dose was excreted, mainly via the feces (85.4% and 84.9%). Further amounts of radioactivity were exhaled. Similar excretion property is also expected for the test item.
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