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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
Absorption rate - dermal (%):
Absorption rate - inhalation (%):

Additional information

Basic toxicokinetics:

There are no studies available in which the toxicokinetic behaviour of reaction mass of 1,1'-(2,2,4-trimethylhexane-1,6-diyl)bis-1H-pyrrole-2,5-dione and 1,1'-(2,4,4-trimethylhexane-1,6-diyl)bis-1H-pyrrole-2,5-dione (MATMD, EC No. 915-671-3) was investigated.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No. 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of MATMD was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017), and of predictions made using the EpiSuite software (US EPA, 2012).


Physico-chemical properties:

MATMD consists of the two main constituents 1H-Pyrrole-2,5-dione, 1,1'-(2,2,4-trimethyl-1,6-hexanediyl)bis- (CAS No. 39979-46-9) and 1H-Pyrrole-2,5-dione, 1,1'-(2,4,4-trimethyl-1,6-hexanediyl)bis- (CAS No. 145967-44-8), which represent stereoisomers. The substance has a molecular weight of 318.3676 g/mol and is a brown solid of ambient colour at 20 °C, with a melting point of 86-92 °C at normal pressure. The water solubility is 70.7 mg/L at 20 ± 0.8 °C and pH 7. The log Pow was measured to be 2.38 and a vapour pressure at 20 °C of 1.76 Pa was determined.



Absorption is a function of the potential for 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).



In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts. This mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) and would otherwise be poorly absorbed (ECHA, 2012).

The physicochemical characteristics (molecular weight, log Pow and the moderate water solubility) of the substance suggest a high potential for oral absorption in the GI tract. Due to the moderate water solubility of 70.7 mg/L and the log Pow of 2.38, a micellar solubilisation of the substance is most likely a very minor mechanism of absorption.

No systemic toxicity was observed in the acute oral toxicity study (90-0530-DGT), the 28-days repeated dose oral toxicity study (2013-0392-DGT) and the oral Reproduction/developmental toxicity screening study (2013-0394-DGR). The clinical signs noted were attributed to the irritating effects of the test substance at the point of contact This would indicate that the substance has a rather low absorption potential or low oral toxicity. The reactivity of the substance may also affect the absorption potential. The potential of a substance to be absorbed in the GI tract may be influenced by chemical changes taking place in GI fluids as a result of enzymes released into the GI tract or due to a certain pH value in an aqueous environment. These changes may alter the physico-chemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2017). Based on the prediction of metabolites obtained with the QSAR OECD Toolbox version 4.3 (OECD, 2019), several hydrolysis products with certain functional groups were simulated for both main constituents, which may occur at various pH within the GI tract. Each 7 hydrolysis products were simulated for both constituents under acidic conditions, 7 under basic conditions and 3 under neutral conditions. Following oral ingestion, MATMD may potentially be hydrolysed in the GI tract, although this will not substantially change the molecular weight. Due to the limited information available on the absorption potential of the parent substance and any hydrolysis products, as a worst-case approach the oral absorption potential is assumed to be high.



The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. The dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if the water solubility of the substance is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2012).

The physico-chemical properties (log Pow, molecular weight and water solubility) of the substance and the molecular weight are in a range that indicate moderate absorption through the skin.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp is thus 9.73E-04 cm/h. Considering the water solubility (70.7 mg/cm³), the dermal flux is estimated to be 0.06876 µg/cm²/h. This prediction indicates a low dermal absorption potential.

 In an acute dermal toxicity study in rats (90-0532-DGT) no mortality, no clinical signs of toxicity and no effect on body weight was noted, suggesting a rather low acute dermal toxicity. However, local skin reactions such as erythema and scales were observed. If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred, although it may only have been a small fraction of the applied dose (ECHA, 2017).

In vivo studies on skin irritation (89-0646-DGT) and skin sensitisation (90-0536-DGT) show that MATMD is skin irritating and highly skin sensitising. Based on the skin irritating properties of MATMD, enhanced penetration due to skin damage is expected. Skin sensitisation effects demonstrated that uptake of the substance must have occurred.


Taking all the available information into account, the substance has a moderate-high potential for dermal absorption.



The substance is a solid with a low vapour pressure of 1.76 Pa, indicating 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.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). 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 particle size distribution shows that 0.8% of the particles are < 100 µm and > 93% of the particles are > 500 µm. The fraction of particles that may be inhaled into the lower airways is negligible.

There are no experimental data on the effects of acute or long-term inhalation exposure. However, the substance has been shown to be irritant via the oral and dermal route, and may potentially cause damage to the mucous membrane in the upper airways that enhances the absorption potential. The log Pow and water solubility indicate that MATMD may be absorbed across the respiratory tract epithelium. 

In applying a worst-case scenario due to the above-mentioned uncertainties, the absorption potential via the inhalation route of exposure is assumed the same as via the oral route of exposure for the substance.


Distribution, bioaccumulation and metabolism:

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).

The oral absorption rate of MATMD is expected to be high, based on the physico-chemical characteristics. Therefore, a substantial fraction of the dose applied will be systemically available for distribution and metabolism.As discussed under oral absorption, MATMD may undergo (enzymatic) hydrolysation in the GI tract. After being absorbed, the parent substance and hydrolysis products would be expected to be widely distributed, due to the molecular weight and the functional groups, which increase the water solubility. However, it is unclear if the reactivity observed at the point of contact in oral and dermal studies may also affect the distribution of the substance to tissues and organs. Due to the lack of lipophilic groups, the substance and the hydrolysis products are not expected to accumulate in adipose tissue.

The substances absorbed from the GI tract will primarily be transported via the portal vein into the liver, where further metabolism is expected. Substances that are absorbed through the pulmonary, respiratory epithelium or through the skin enter the systemic circulation directly before they are transported to the liver and metabolised. The potential metabolites following enzymatic metabolism of the main constituents of the test substance were predicted using the QSAR OECD Toolbox v.4.3.1 (OECD, 2019).This QSAR tool predicts which metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the GI tract. For each of the main components, 20 metabolites were predicted in the ‘In vivo rat metabolism’ simulation, including many secondary metabolites. Primarily, the opening of the pyrrol ring structures or hydroxylation of a methyl group is predicted as a first step. The metabolites are the result of enzymatic oxidation or hydroxylation processes. There were no predictions for metabolites in the ‘Rat liver S9 metabolism’ simulation or in the skin. Up to 55 and 57 metabolites, respectively, were predicted to result from microbiological metabolism of the two main constituents. The high number includes many minor variations in the c-chain length and number of carbonyl- and hydroxyl groups; reflecting the many microbial enzymes identified. Not all of these reactions are expected to take place in the human GI-tract.

There is no indication that MATMD is activated to reactive intermediates under the relevant test conditions. All three experimental studies performed on genotoxicity (Ames test, micronucleus test and mouse lymphoma assay) were negative, with and without metabolic activation (2008-0222-DGM, 2013-0398-DGM and 2013-0396-DGM).




MATMD and possibly hydrolysis products were predicted to be absorbed in the GI tract, from where it enters the systemic circulation. The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (ECHA, 2017). Urinary excretion is favoured by the moderate water solubility, as well as the low molecular weight (< 500 g/mol) of the substance.

As described above, to the extent that the substance reaches the liver and other tissues for metabolism, extensive phase I metabolism is predicted for the two constituents of the substance.. The biotransformation makes the metabolites more susceptible to phase II metabolism processes, in which the metabolites are conjugated to polar molecules such as glucuronic acid, sulfates or amino acids. 

Most of the conjugated, more water soluble molecules are filtered out of the blood by the kidneys and undergo renal excretion. Conjugation to glucuronide or glutathione derivates may also favour biliary excretion and pass the intestine before they are excreted in the faeces.

In addition, the fraction of substance that is not absorbed in the GI tract will be excreted via the faeces.



ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0.


US EPA (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA. Downloaded from:



OECD (2019) OECD QSAR Toolbox: Prediction of metabolites or hydrolysis products. Version 4.3.1. Prediction performed 04.12.2019.