1,1'-(4-methyl-1,3-phenylene)bis-1H-pyrrole-2,5-dione

Endpoint summary

Description of key information

Experimental toxicokinetic studies are not available for 2,4 -Bismaleimidotoluene.

The log Kow of -0.0036 and the molecular weight of 286.26 g/mol are suggestive of oral absorption from gastro-intestinal tract, by dermal route or from the lungs.
Due to the lack of experimental data, 100% absorption by inhalation and 50% absorption by oral and dermal absorption is assumed as worst case default for chemical safety assessment.

- Hydrolysis study conducted according to OECD guideline 111; GLP, most prominently the heterocyclic moieties of 2,4-Bismaleimidotoluene are hydrolysed first resulting in several transformation products. The loss of one heterocyclic ring and the subsequent decomposition of the second ring was also detected. Further degradation by intermediary metabolism.

Expert statement: Metabolism, distribution, excretion: hydrolysis was shown resulting in cyclic amines which are hydroxylated, glucuronidated and expected to be rapidly excreted via the urine.

Based on physicochemical properties, no potential for bioaccumulation is to be expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Data from in vitro or in vivo studies, which were designed to identify the toxicokinetic properties of 2,4-Bismaleimidotoluene, are not available. Therefore, the toxicokinetic behaviour will be assessed based on its physico-chemical and toxicological properties.

 

Absorption:

Oral:

There are several studies available in which the systemic effects of 2,4-Bismaleimidotoluene were investigated.

In an acute oral toxicity study, repeated dose toxicity study (28-days), and a reproduction/developmental toxicity screening study according to OECD guideline 407, GLP compliant, administration of 10, 30 and 100 mg/kg bw 2,4-Bismaleimidotoluene caused treatment related effects which were considered to be a reaction to local toxicological effects and due to their reversibility were not considered to be relevant to humans. There were no other, non-irritating effects related to the substance that would substantiate the absorption of 2,4-Bismaleimidotoluene.

Similar, in an acute toxicity study according to OECD guideline 401, GLP, rats were administered 2000 mg/kg bw and no mortality occurred during a 14 days observation period. In this study the most prominent adverse signs were hunched position and ruffled fur. Both effects were fully reversible within the 14 day observation period and thus, considered to be local irritating effects to mucous membranes. Furthermore, in a reproduction/developmental screening study according to OECD guideline 421, GLP male and female (pregnant) were administered orally up to 60 mg/kg bw for 63 days. Neither the parental animals nor the pups showed toxic effects that were substance-related. In this study also premature deaths occurred but similar to the repeated dose toxicity study these effects showed no dose-response relationship and cannot histopathologically be correlated to effects other than local irritating effects.

Additionally, in an eye irritation study conducted according to OECD guideline 405, GLP-compliant, 0.1 g 2,4-Bismaleimidotoluene was instilled into the conjunctival sac of one eye three rabbits. The irritating effects were recorded at 24, 48 and 72h after exposure. 2,4-Bismaleimidotoluene was classified according to GHS criteria Category 1 to cause severe damage to the eye. Therefore, it can be assumed that 2,4-Bismaleimidotoluene exhibits irritating effects to mucous membranes.

Since only local effects were detected in the above mentioned studies, these results are not sufficient to prove an absorption via the GI tract, the absorption of 2,4-Bismaleimidotoluene can only be assessed via its physico-chemical properties. However, based on the available studies the uptake of 2,4-Bismaleimidotoluene cannot be fully excluded.

2,4-Bismaleimidotoluene has a molecular weight of less than 500 g/mol (282.26 g/mol) and a log Kow of -0.0036 and log P values between -1 and 4 are in general favourable for absorption subsequent to oral ingestion. 2,4-Bismaleimidotoluene contains no ionisable groups and therefore the unionized from prevails during the gastrointestinal passage; this property also favours absorption. However, this absorption will mainly take place by passive diffusion. Absorption via aqueous pores is rather unlikely due to its size which is above the size for uptake by aqueous pores (200 g/mol). A metabolism prior to uptake may also occur by the gut flora or enzymes in the GI mucosa, this could favour or counteract absorption as well. However, absorption was not clearly shown by studies mentioned above but it cannot also be ruled out, thus, also due to the lack of toxicokinetic data an oral absorption rate for 2,4-Bismaleimidotoluene of 50% is assumed for safety assessment for both animals and humans.

 

Inhalation:

In an acute inhalation toxicity study in female/male Wistar rats according to OECD TG 403 (adopted May 12th, 1981); RL1; GLP; the animals were exposed to 0.021, 5.77, 15.5 and 28.1 mg/L 2,4-Bismaleimidotoluene (a.i.) for 4 h.At a concentration of 5.77 mg/L three female animals and all of the animals receiving 28.1 mg/L for 4 h died within the first 24 h after exposure.The predominant clinical signs that occurred after exposure were irregular/accelerated respiration, eyelid closure and reddish nasal discharge supporting the assumption that 2,4-Bismaleimidotoluene is readily taken up by the respiratory tract and furtherindicates that the adverse effects are caused by local toxicity.The LC50 for male/female rats = 0.09 mg/L air. The local toxicity was also shown in an eye irritation study according to OECD guideline 405 in rabbits as mentioned in the above section. Since the adverse effects that occurred during the observation period were not fully reversible within 21 days in at least one animal 2,4-Bismaleimidotoluene was classified to cause serious eye damage.

These results support the assumption that the test substance is corrosive to mucous membranes.

2,4-Bismaleimidotoluene is a solid at room temperature and melts at 174-176°C together with a low vapor pressure of 3.00E-010 Pa, substance evaporation and uptake of aerosols by inhalation is unlikely. However, the uptake after direct inhalation of substance dust particles may occur in humans due to a mean diameter of 50.1 µm which is almost the threshold value for particles to reach the thoracic region (< 50 µm) and which are definitively inhaled (inhalation threshold < 100 µm). As indicated by the negative log Kow and a moderate water solubility (60 mg/L) 2,4-Bismaleimidotoluene is assumed to be readily dissolved into the mucous lining of the respiratory tract and is therefore unlikely to be coughed or sneezed out of the body. It will be taken up and possibly metabolised to an excretable, hydrophilic derivative. A deposition into lymphoid tissues is also rather unlikely.

Thus, for precautionary reasons the estimated absorption of 2,4-Bismaleimidotoluene via the respiratory tract is 100%.

 

Dermal:

There are no acute dermal toxicity studies available, thus, the toxicokinetic properties of 2,4-Bismaleimidotoluene regarding dermal absorption are assessed by its physico-chemical properties. Dermal absorption may be rather unlikely due to its low molecular weight (282.26 g/mol), its low log Kow (-0.0036) and its water solubility (60 mg/L), but dermal absorption of 2,4-Bismaleimidotoluene cannot completely excluded.

In contrast to oral absorption and uptake via inhalation no irritant effects were detected. In a study according to OECD guideline 404 the test item was applied to the intact skin of three rabbits. Although the substance was considered to colour the skin, no other adverse effects were observed during the 72 h observation period and thus, the substance is not classified according to Regulation (EC) 1272/2008 (CLP) as irritating to the skin in contrast to the mucus membranes in the eye and the respiratory tract.

Thus, in lack of detailed dermal penetration data and for precautionary reasons a dermal absorption rate of 50% is assumed as worst case default value.

 

Distribution:

As a small molecule a wide distribution can be expected. No information on potential target organs are available. However, as 2,4-Bismaleimidotoluene exhibits a low molecular weight and predominantly occurs in a unionized form it may readily diffuse across biological membranes.

 

Metabolism:

There are no data on the metabolism of 2,4-Bismaleimidotoluene. It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone.

Based on structure the substance may undergo spontaneous or enzymatic hydrolysis which was also shown during a study according to OECD guideline 202 in Daphnia magna. In this study analysis of the substance filtrate showed that measured concentrations decreased by approximately 30% during the first 4-hour test period and to an extent of 80% after 24 hours. This decrease was related to the instable hydrolytic character of the substance in water.

A hydrolysis study conducted according to OECD guideline 111; GLP, is available. 2,4-Bismaleimidotoluene was found to be hydrolytically instable at all tested temperatures and pH. However, acidic conditions seem to stabilize 2,4-Bismaleimidotoluene in comparison to a high pH. Major transformation products have been detected in any test condition. Based on these results most prominently the heterocyclic moieties of 2,4-Bismaleimidotoluene are hydrolysed first resulting in Transformation product (2Z, 2´Z)-4,4´-[(4-methylbenzene-1,3-diyl)diimino]bis(4-oxobut-2-enoic aicd), ((2Z)-4-{[5-(2,5-dioxo-2,5-dihydro-1H-pyrole-1-yl)-2-methylphenyl]amino}-4-oxobut-2-enoic acid and (2Z)-4-{[3-(2,5-dioxo-2,5-dihydro-1H-pyrrole1-yl)-4-methyphenyl]amino}-4-oxobut-2-enoic acid). Similarly, the loss of one heterocyclic ring and the subsequent decomposition of the second ring was also detected. Since these reactions also occurred at pH 7, it is likely 2,4-Bismaleimidotoluene is hydrolysed to (2E)-but-2-enedioic acid and (2Z)-but-2-enedioic acid which are considered to be metabolised during the intermediary metabolism. The above mentioned transformation products are assumed to undergo further hydrolysis of the carboxylic acids which in turn would leave a cyclic amine and (2E)-but-2-enedioic acid or (2Z)-but-2-enedioic acid.

Cyclic amines are known to be acetylated by N-acetylases and adjacent hydroxylated by CYP450-monooxygenases. Subsequently, the hydroxyl-group is glucuronidated and renally excreted.

Due to its structure, hydrolysis may not necessarily be required for catabolism of 2,4-Bismaleimidotoluene, a direct hydroxylation via CYP450 monooxygenases is also possible. After hydroxylation and glucuronidation, as described above, 2,4-Bismaleimidotoluene is renally excreted.

Excretion:

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces. Excretion by exhalation does not seem to be relevant route of excretion based on the physico-chemical properties of the substance. However, since there is the possibility that several metabolites can occur due to partial or full hydrolysis renal and biliary excretion must be assumed.

 

Bioaccumulation

Based on log Kow of -0.0036 the substance is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.