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Endpoint summary

Description of key information

Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate (EC 950-225-1) is considered to have a low dermal absorption rate. Inhalation exposure is expected to be very low. A conclusion on the oral absorption potential cannot be drawn based on the available data. The substance is considered to be widely distributed within the water compartment of the body, if systemic absorption takes place at all. Based on the physicochemical and toxicological characteristics no accumulation in the body is expected and excretion mainly via urine is considered.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behavior of Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate (EC 950-225-1) has been investigated. Also for the structurally related substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid (CAS 2241455-89-8) no information on the disposition and metabolism in experimental animals or humans is available.

 

The target and source substance are structurally very similar, i.e. they share the same anion species- succinate moiety connected to one of the nitrogen atoms of the pyrazole ring with two methyl groups attached. The difference between the target and source substance is that the target is the dipotassium salt of the source. Both substances are well soluble, therefore once dissolved into water, the common anion species will be released from dissociation. The non-common cation species, H⁺ or K⁺ in the target and source substances. Potassium ions are not considered to cause adverse effects in the human body and/or environmental species or to influence the suitability of the read-across, since potassium is an essential element abundantly present in nature. Based on this, comparable toxicokinetic behavior is expected for Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate and Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid.

 

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, 2017), assessment of the toxicokinetic behaviour of the substance Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate was 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.

Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate is a light beige powder with a molecular weight of 288.38 g/mol. The substance has a low vapour pressure of 0.0068 Pa at 20°C. The log Pow is -2.5 at 20°C and the water solubility is 79500 mg/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, 2017).

 

Oral

Based on the physico-chemical properties of Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate absorption is possible due to the low molecular weight < 500 g/mol. Due to the high water solubility (79500 mg/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 -2.5), absorption by passive diffusion may also be limited, as the substance is not considered to easily cross biological membranes. Data from an acute oral toxicity studies and a repeated oral toxicity study (OECD 422) with the analogue substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid revealed no test item related effects up to the limit doses. Therefore, no conclusion can be drawn from this study regardingoral absorption, as absence of effects could be due to chemical-intrinsic or toxicokinetic properties.

 

Dermal

There are no data available on dermal absorption of Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate.

On the basis of the following considerations, the dermal absorption of the substance is considered to be low.

The molecular weight of the substance > 100 g/mol (288.3833 g/mol) does not favour dermal uptake. Furthermore, a substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. However, if water solubility is above 10 g/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Since the substance is highly soluble in water solubility (79500 mg/mL) and has a log Pow below 0 (-2.5), dermal absorption is assumed to be low.

The dermal permeability constant Kp of the substance was estimated to be 8.61E-7 cm/h using DermwinTM and taking into account the log Pow and molecular weight. Furthermore, the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated to be 0.06846 µg/cm²/h indicating a low dermal absorption. Data from an acute dermal toxicity study with the read-across substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid revealed no effects of the test substance up to the limit dose of 2000 mg/kg bw. 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 very low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance is not significant.

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, 2017). The MMAD is not known for the substance, but since the substance is marketed in a non-solid or granular form the particle size is not considered relevant. 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, 2017). Based on the hydrophilic properties of Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate 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 dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate itself. Under aqueous conditions in the body the cations (K⁺) of DMPSA-K2 will be dissociated from the anion and the common dissociation product is the anionic moiety (DMPSA).

Prediction of compound metabolism based on physico-chemical data is very difficult. The QSAR software (OECD toolboxv4.3) using the following profilers: Hydrolysis simulator (acidic and basic) version 3.5, Rat liver S9 metabolism simulator version 3.6, in vivo Rat metabolism simulator version 3.3 and Skin metabolism simulator version 3.4) was used for prediction of metabolites (knoell Germany GmbH, 2019). Predictions were performed for the two constituents 2-(3,4-dimethyl-1H-pyrazol-1-yl)butanedioate and 2-(4,5-dimethyl-1H-pyrazol-1-yl)butanedioate in a separate manner. Furthermore, the potassium ions (K+) have been removed from the two constituents because the metabolic profilers of the OECD QSAR Toolbox are not designed to handle salts and disconnected structures in general. Thus, the predictions are the same for target and source substance. Both constituents were predicted to form one hydrolysis product under acidic and basic conditions. The rat liver S9 metabolism simulator and the in vivo rat metabolism simulator predicted the same metabolites from the same parent substance, but the in vivo rat metabolism simulator predicted more metabolites. For 2-(3,4-dimethyl-1H-pyrazol-1-yl)butanedioate 6 metabolites were predicted using the rat liver S9 metabolism simulator version 3.6 and 9 metabolites were predicted using the in vivo rat metabolism simulator version 3.3. For the other constituent 2-(4,5-dimethyl-1H-pyrazol-1-yl)butanedioate 4 metabolites were predicted using the rat liver S9 metabolism simulator version 3.6 and 9 metabolites were predicted using the in vivo rat metabolism simulator version 3.3. Some predicted metabolites included oxidation of the methyl-moiety to an alcohol, aldehyde or carboxylic acid.

There is no indication that Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate 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 Ames test was negative, with and without metabolic activation. In addition, the cytogenicity and mutagenicity studies in mammalian cells with the analogue substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid revealed not genotoxic potential with and without metabolic activation.

 

Excretion

Excretion of Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate is expected to occur mainly via urine. The molecular weight (< 300 g/mol) and a good water solubility are properties favouring urinary excretion. Based on the physico-chemical properties the test substance is not considered to accumulate in the body.

 

References:

ECHA (2017), Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 3.0 June 2017

 

knoell Germany GmbH (2019),OECD QSAR Toolbox v4.3 metabolite prediction of Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethy-1H-pyrazol-1-yl) succinate(CAS No.n.a./ EC No.950-225-1), Report number: 109833/1