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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance Reaction mass of Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies evaluating the toxicokinetic properties of the substance available.

Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid is a white crystalline powder with a molecular weight of 212.20 g/mol. The substance has a low vapour pressure of 0.002 Pa at 25°C. The log Pow is -2.2 at 21°C and the water solubility is 15.7 g/L at 20°C.

Absorption

Absorption is a function of the potential of a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

Oral

Based on the physico-chemical properties of Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid absorption is possible due to the low molecular weight < 500 g/mol. Due to the high water solubility (15.7 g/L) absorption by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Water-soluble substances will readily dissolve into the gastrointestinal fluids. In addition, as the substance is hydrophilic (log Pow < -2.2) and is available in an ionic form, absorption by passive diffusion may also be limited, as the substance is not considered to easily cross biological membranes. Data from acute and repeated oral toxicity studies (Leonie, 2012a; Schleh, 2013) revealed no test item related effects up to the limit doses. Therefore no conclusion can be drawn from these studies regarding toxicokinetic behaviour.

Dermal

There are no data available on dermal absorption of Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid. On the basis of the following considerations, the dermal absorption of the substance is considered to be low. Regarding the octanol/water partition coefficient of < -2.2 in combination with the fact that the molecule is ionic, a low dermal absorption rate is anticipated based on expert judgement. The dermal permeability constant Kp of the substance was estimated to be 3.63E-6 cm/h using DermwinTM and taking into account the log Pow and molecular weight. Further on the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated similar to the approach taken by Kroes et al. (2007) and yielded in a value of 0.05696 µg/cm²/h. This flux value can be assigned to a low dermal absorption of 10% (Kroes at al., 2007).

Data from an acute dermal toxicity study revealed no effects of the test substance up to the limit dose of 2000 mg/kg bw (Leonie, 2012b). Therefore no conclusion can be drawn from this study regarding toxicokinetic behaviour, as absence of effects could be due to chemical or toxicokinetic properties.

 

Inhalation

The test substance has a very low vapour pressure < 0.01 Pa at 25 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

The substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the formulated substance is sprayed. But based on the MMAD of 107.34 µm for the test substance, inhalation is supposed to be rather low. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2012).

In conclusion, the inhalative absorption of the test substance is considered to be not higher than through the intestinal epithelium.

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, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2012).

Based on the hydrophilic properties of Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid the substance is supposed to be widely distributed within the water compartment of the body, if systemic absorption takes place at all.

Metabolism

No metabolism studies are available with Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid itself. Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo.

Software supported QSAR of liver metabolism (OECD toolbox v3.0) revealed some oxidative metabolites of the test substance. Some suggested metabolites included oxidation of the methyl-moiety to an alcohol or aldehyde. Other calculated metabolites were formed by oxidation of C2/C3 atoms of the succinic acid moiety leading to form a double bond. In addition, conjugation of the alcohol or an aromatic nitrogen atom is possible.

There is no indication that Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid is activated to reactive metabolites under the relevant test conditions. There was no evidence for differences in toxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) were negative, with and without metabolic activation (Scheib, 2012; Trenz, 2013; Zeller, 2013).

 

Excretion

Excretion of Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid and the oxidised metabolites is expected to occur mainly via urine. The molecular weight (< 300 g/mol), a good water solubility and ionisation of the molecule at the pH of the urine are properties favouring urinary excretion. After conjugation of the parent substance or the oxidised metabolites with glucuronic acid, excretion via the faeces could also occur, as the molecular weight of the conjugates is > 300 g/mol.