Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance N,N′-m-phenylenedimaleimide  is a yellow powder. It is an organic mono-constituent with a purity of ≥99.6% with 1 minor impurity (≤0.4%).

A full ADME toxicokinetic study in the rat is not available.  The toxicokinetic analysis is based on physicochemical data and in vivo animal models. In vivo studies in rats covering the oral routes are available (acute oral toxicity study and combined repeated dose toxicity and reproduction/developmental toxicity screening study). A skin sensitisation study in mice is available (local lymph node assay). An acute inhalational toxicity study in rats is available. Further details on endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical properties and information in the dossier, N,N′-m-phenylenedimaleimide is expected to be absorbed well after oral and inhalation exposure. Dermal absorption is likely to be lower. N,N′-m-phenylenedimaleimide and its by-products may be distributed throughout the body and excreted in the urine.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

1. Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of N,N′-m-phenylenedimaleimide in the body.

The hydrolysis data indicates that N,N′-m-phenylenedimaleimide hydrolyses very quickly at ph 4, 7 and 9 (maximum t(1/2) ph 4 = 0.48 day at 20°C). The temperatures at which this test was conducted (20 - 30°C) are lower than expected in vivo, however, it may give an indication that the parent compound may only be present in the body for a limited period of time. Hence, the caveat any that toxicokinetic prediction based on the characteristics of the parent compound, N,N′-m phenylenedimaleimide, may be of limited relevance, is included in this report.

Absorption - oral

The molecular weight (268.23 g/mol) and water solubility of 5007 mg/L (estimated) are favourable for oral absorption of N,N′-m-phenylenedimaleimide. The log P of 0.67 suggests that N,N′-m-phenylenedimaleimide is in the favourable range for absorption by passive diffusion (log P: -1 to 4).

Absorption – dermal

The molecular weight of 268.23 g/mol is above the range for favourable dermal absorption (<100 g/mol). The water solubility of 5007 mg/L (estimated) indicates that moderate to high uptake may be expected however the lipophilicity (log P of 0.67) and physical state (solid) indicate that dermal absorption of N,N′-m-phenylenedimaleimide is likely to be low.

Absorption – inhalation

The particle size distribution report for N,N′-m-phenylenedimaleimide indicates a range of 0.142 μm-79.621 μm (d(0.1): 3.363 μm  d(0.5): 11.131 μm  d(0.9):  32.874 μm).  This indicates that 100% of the particles are available in the inhalable fractions of air (<100 μm). Particles with aerodynamic diameters of above 1-5 μm have the greatest probability of settling in the nasopharyngeal region whereas particles with aerodynamic diameters below 1-5 μm are most likely to settle in the tracheo-bronchial or pulmonary regions. As there are fractions in both these categories, the substance is likely to be distributed throughout the respiratory tract upon inhalation. Greater than 50% of particles will be able to penetrate the alveolar region of the respiratory tract (<15 µm). As a water-soluble dust (5007 mg/L (estimated)), N,N′-m-phenylenedimaleimide would readily diffuse/dissolve into the mucus lining the respiratory tract and as a lipophilic substances (log P 0.67) would then have the potential to be absorbed directly across the respiratory tract epithelium. Based on the water solubility (5007 mg/L (estimated)), log P (0.67) and particle size, there is potential for absorption via the inhalational route.

Distribution

The molecular weight (268.23 g/mol) and water solubility (5007 mg/L (estimated)) of N,N′-m-phenylenedimaleimide are favourable for wide distribution. A substance with a log P >0 is also favourable for distribution. A substance with a log P <3 is unlikely to accumulate in adipose tissue with intermittent exposure.

Metabolism/Excretion

Based upon the molecular weight of 268.23 g/mol, water solubility of 5007 mg/L (estimated) and hydrolysis data, it is likely that metabolites of N,N′-m-phenylenedimaleimide are excreted mainly in the urine.

2. Information from other studies in the dossier

Absorption - oral

In the acute oral gavage toxicity study in rats, all animals were dead by Day 4 at 2000 mg/kg bw; at 300 mg/kg bw, there were no mortalities. At necropsy of the 2000 mg/kg bw group, dilated lumen and liquid contents of stomach were observed in all animals, and red patches of glandular stomach and reddish contents of small intestine were observed. Some findings suggesting digestive injury were considered to be treatment-related effects. There were no changes noted at necropsy in the 300 mg/kg bw group. The LD50 (male/female) was >300-2000 mg/kg bw.

In the combined repeated dose and reproduction/developmental toxicity screening test in rats, death occurred in 4 females and 2 males at the highest dose, 240 mg/kg bw/day. Effects on urinalysis (males only) and blood chemistry were noted at 240 mg/kg bw/day. There were no effects on body weight, food consumption, hematologic parameters, blood coagulation or organ weight. Histopathologically, blood absorption by the mesenteric lymph nodes was observed in all of the animals which were found dead, and brown pigments in the mesenteric lymph nodes, haemorrhage from the forestomach, oedema, polymorphonuclear cell infiltration and inflammation in the glandular stomach in some of them. From these pathological findings, the cause of death was considered to be gastric injury and dysfunction of the digestive tract by the test substance. Squamous cell hyperplasia in the forestomach was noted in 4/4 dead females at 240 mg/kg bw/day. The following histopathological findings also confirmed the presence of the gastric injury by the test substance: blood absorption by the mesenteric lymph nodes, brown pigments in the mesenteric lymph nodes, squamous cell hyperplasia and an increase in apoptosis in the forestomach, hemorrhage from the forestomach, proliferation of surface mucous cell in the glandular stomach in males or females in the 60 or 240 mg/kg group. An increase in mitosis in the glandular stomach was observed in animals of both sexes given 15 mg/kg or more. This finding was considered to be an effect of the test substance but was concluded to be toxicologically meaningless because there were no other findings suggestive of gastric injury in those groups. The NOAEL for both sexes was 15 mg/kg bw/day and the NOEL was <15 mg/kg bw/day.  In terms of reproductive/developmental toxicity, there were no adverse effects on reproductive ability, including delivery and lactation. Observation of pups revealed no effects of the test substance on viability, body weights, morphology or necropsy findings. The NOEL and NOAEL for reproductive/developmental toxicity (parental and F1) were considered to be 240 mg/kg/day, because there were no treatment-related changes in all parameters.

These studies indicate that there is systemic absorption after oral administration. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Absorption – dermal

The local lymph node assay (LLNA) for skin sensitisation in mice showed that N′-N-phenylenedimaleimide was not irritating to the skin at any dose (50 %, 5 %, 0.5 % (w/v)) and there were no mortalities, adverse clinical observations or changes in body weight. The LLNA study indicated that N′-N-phenylenedimaleimide is sensitizing, so there is some uptake via the dermal route. The available in vivo dermal toxicity data together with the physicochemical data indicates that some dermal absorption occurs.  The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption – inhalation

An acute inhalational toxicity study in rats is available. A respirable dust aerosol fraction that might reach 88 -99% of the alveolar region was obtained. (MMAD 1.3 μm – 3.3 μm; GSD 2.6 – 4.3). As the dosing increased, the number of mortalities increased (0.006, no deaths; 0.012, 0.043 mg/l, 2/10 deaths by Day 1; 0.11, 0.29 mg/l, 7/10 deaths by Day 2). There was also a dose-dependent increase in clinical signs including effects on respiration, squatting position, ruffled fur, high stepping gait, and deteriorated general state. In animals that died spontaneously or were sacrificed in a moribund state, pathological findings were general congestion, focal hyperemia in lungs and some animals with emphysema and dark adrenals. In sacrificed animals there were no pathological findings noted. The LC50 Combined was 0.089 mg/l (0.044 mg/l - 0.256 mg/l). For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted based on the particle distribution data and results from the acute inhalational study in rats.

Distribution/Metabolism/Excretion

The acute oral and combined repeated dose and reproduction/developmental toxicity screening test in rats indicate that treatment-related histopathological effects were noted in the digestive tract. Based on the physicochemical and in vivo data, it is likely that metabolites of N,N′-m-phenylenedimaleimide are excreted mainly in the urine.