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EC number: 202-945-6
CAS number: 101-48-4
studies are available. The molecular weight, physicochemical properties
incl. water solubility and octanol-water partition coefficient of the
substance suggest that oral, inhalative and dermal absorption occur.
Widely distribution within the water compartment of the body after
systemic absorption is because of lipophilicity of the test substance
not expected. However, the distribution into cells particularly in fatty
tissues is likely. Based on its log Pow the test substance is not
considered to accumulate. The test substance might be metabolised after
absorption. Excretion predominantly via the urine is expected.
with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and
with Guidance on information requirements and chemical safety assessment
Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the
toxicokinetic behaviour of the substance is conducted to the extent that
can be derived from the relevant available information on
physicochemical and toxicological characteristics. There are no studies
available evaluating the toxicokinetic properties of the substance.
substance is a clear colourless liquid at 20°C with a molecular weight
of 166.22 g/mol and a water solubility of 3.9 g/L at 20°C. The substance
has a vapour pressure of 2.24 hPa at 20°C and the log Pow is 2.23 at 24.7°C.
routes by which the test substance can enter the body are via the lung,
the gastrointestinal tract, and the skin. To be absorbed, test
substances must transverse across biological membranes either by active
transport mechanisms or - as being the case for most compounds - by
passive diffusion. The latter is dependent on compound properties such
as molecular weight, lipophilicity, or water solubility (ECHA, 2014).
low molecular weight (MW ≤ 500) and moderate lipophilicity (log Pow
values of -1 to 4) are favourable for membrane penetration and thus
absorption. The molecular weight of the test substance is relatively low
with 166.22 g/mol, favouring oral absorption of the compound. This is
supported by the determined log Pow values of 2.23, being advantageous
for oral absorption. In addition the water solubility of 3.9 g/L leading
to a ready dissolving of the compound in the gastrointestinal fluids
favours oral absorption. Moreover, the observation of systemic toxicity
following exposure by any route is an indication for substance
absorption; however, this will not provide any quantitative information.
In an acute
oral toxicity study conducted with the test substance in rats no
mortalities were observed at 2000 mg/kg bw until the end of the study
but slight signs of toxicity noted were abnormal gait. No abnormalities
were noted at necropsy at termination of the study. In this acute oral
toxicity study in rats a LD50 cut-off value of ≥ 5000 mg/kg bw was found.
a repeated-dose oral toxicity study in rats was conducted with the test
substance (2017). In a dose range-finding study, animals were treated at
doses of 50, 200 and 800 mg/kg bw/day for 14 days. At 800 mg/kg bw/day
salivation and soiled perineal region were observed and necropsy
revealed increased liver weights in males and females. In the main
study, animals were administered the test substance at dose levels of
60, 200 and 600 mg/kg bw/day. No substance- related mortality was
observed within the study period. Increased liver weights in males at
600 mg/kg bw/day and in females at 200 and 600 mg/kg bw/day were noted.
Hepatocellular hypertrophy was observed in animals of both sexes at 200
and 600 mg/kg bw/day. This effect was regarded as an adaptive response
to the test substance and was considered not to be harmful to the
animals. Based on available data from the acute oral and repeated dose
toxicity study, slight toxicological signs and adaptive responses to the
test substance were observed and thus absorption of the test substance
via the gastrointestinal tract has evidently occurred.
uptake of liquids and substances in solution is generally expected to be
higher than that of dry particles. Molecular weights below 100 g/mol
favour dermal uptake, while for those above 500 g/mol the molecule may
be too large. Thus, for the molecular weight level of the test substance
dermal uptake can be expected to be moderate. The Log Pow value of the
test substance is optimal for dermal absorption. In addition, the water
solubility is sufficiently high for partitioning from the stratum
corneum into the epidermis indicating dermal uptake. The dermal
permeability constant Kp of the substance was estimated to be 0.00555
cm/h using DermwinTM (v.2.01) and taking into account an estimated log
Pow of 2.23 and the molecular weight of 166.22 g/mol. Thus the
absorption of the test substance by the dermal route is anticipated to
be moderate to high and comparable to oral absorption at most.
Data from an
acute dermal toxicity study revealed no effects of the test substance up
to the limit dose of 2000 mg/kg bw (2015).
Pow values (between -1 and 4) are favourable for absorption directly
across the respiratory tract epithelium by passive diffusion. The test
substance has a vapour pressure of 2.24 hPa at 20 °C and therefore its
volatility is considered low (< 500 Pa). Thus, under normal use and
handling conditions, inhalation exposure and availability for
respiratory absorption of the substance in the form of vapour can be
No data are
available regarding distribution. Distribution of a compound within the
body depends on the physicochemical properties of the substance;
especially the molecular weight, the lipophilic character and the water
solubility. In general, the smaller the molecule, the wider is the
distribution. If the molecule is lipophilic (log Pow > 0), it is likely
to distribute into cells and the intracellular concentration may be
higher than extracellular concentration particularly in fatty tissues
Thus, due to
the small molecular weight (166.22 g/mol) and a moderately lipophilic
character (log Pow 2.23) distribution into cells and the intracellular
concentration may be higher than the extracellular concentration
particular in fatty tissues, if the substance is absorbed systemically.
Substances with log Pow values of 3 or less would be unlikely to
accumulate with the repeated intermittent exposure patterns normally
encountered in the workplace but may accumulate if exposures are
studies are available with the test substance itself. Prediction of
compound metabolism based on physicochemical data is very difficult.
Structure information gives some but no certain clue on reactions
occurring in vivo. The potential metabolites following enzymatic
metabolism were predicted using the QSAR OECD toolbox (v3.4, OECD,
2016). This QSAR tool predicts which metabolites may result from
enzymatic activity in the liver and in the skin, and by intestinal
bacteria in the gastrointestinal tract. 8 hepatic and 3 dermal
metabolites were predicted for the test substance, respectively.
Primarily, hydrolysis of the substance may occur in the liver. In
general, the introduction of hydroxyl groups by hepatic phase
I-metabolism leads to higher water solubility and makes the substances
more susceptible to metabolism by phase II-enzymes. Up to 64 metabolites
were predicted to result from all kinds of microbiological metabolism
for the test substance. Most of the metabolites were found to be a
consequence of the degradation of the molecule. There was no evidence
for differences in genotoxic potencies due to metabolic changes in in
vitro genotoxicity tests. The test substance did not induce gene
mutations in the Ames test (King, 1999 and 2001) and at the HPRT locus
in V79 cells with and without metabolic activation and did not induce
micronuclei in human lymphocytes with and without metabolic activation
(King, 2002 and Sokolowski, 2015).
conclusions on excretion of a compound can be drawn based on
physicochemical data. Due to metabolic changes, the finally excreted
compound may have few or none of the physicochemical properties of the
parent compound. In addition, conjugation of the substance may lead to
very different molecular weights of the final product. The molecular
weight (< 300 g/mol) and the water solubility of the molecule are
properties favouring excretion via urine. Thus the test substance is
expected to be excreted predominantly via the urine.
Guidance on information requirements and chemical safety assessment –
Chapter 7c: Endpoint specific guidance. European Chemicals Agency,
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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