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EC number: 213-551-9 | CAS number: 976-56-7
Table 1: Radioactivities, the average relative and equivalent concentrations of the orally administered test substance in the blood of rats after different time points.
Radioactivity of blood [nCi/g] at time after administration [h]
Relative standard deviation (%)
Average relative concentration
Average equivalent concentration
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)]
Number of animals
Route of excretion
Table 3. Summary of the average radioactivity amounts in %, of the average relative (P) and equivalent concentrations (C) after 168 h.
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]
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.
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).
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.
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.
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).
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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