N,N'-(methylenedi-p-phenylene)bis[hexahydro-2-oxo-1H-azepine-1-carboxamide]

Endpoint summary

Description of key information

The main relevant exposure route for Grilbond IL-6 is via inhalation of dust due to its particle size. Considering the physico-chemical properties, i.e., high molecular weight, insolubility in water and organic solvents it is concluded that Grilbond IL-6 has very low bioavailability. Distribution of Grilbond IL-6 is limited to liver and kidney. Metabolism involves transformations of the urea carbonyl groups leading to derivatives based on caprolactam and hydrolysed 4,4-MDI which are excreted after conjugation with glucuronic acid, sulphate, glutathione and other endogenous groups via urine or faeces. The available data indicate that Grilbond IL-6 has low toxicity (NOEL in subchronic oral toxicity study, using rats: 1000 mg/kg bw/d) and a low bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

Scientific Assessment Report of Toxicokinetic Behaviour of Grilbond IL-6

 

1. Introduction

Grilbond IL-6 is a bonding agent for the treatment of polyester cord used in rubber goods such as tyres, conveyor belts, v-belts, hoses, canvas. The active ingredient in Grilbond IL-6 is a blocked diisocyanate, which is produced from diphenylmethane diisocyanate and caprolactam. Grilbond IL-6 is supplied either as powder or as a storage stable aqueous dispersion. At room temperature Grilbond IL-6 is completely inert and safe to handle. Above 170 °C, under process conditions, Grilbond unblocks and liberates the active isocyanate component which creates the required adhesion activation.

Identification of the substances

Chemical name: N,N'-(methylenedi-p-phenylene)bis[hexahydro-2-oxo-1H-azepine-1-carboxamide]

Synonyms: 1H-Azepine-1-carboxamide,N,N'-(methylenedi-4,1-phenylene)bis[hexahydro-2-oxo-oxybenzone]

CAS No: 54112-23-1

EINECS: 258-981-8

Molecular Formula: C27H32N4O4

Molecular Weight: 476.57 g/mol

 

2. Available information of the substance

Physico-chemical Data

Physical state: white powder at 20 °C

Melting point: 177 °C (449 K)

Relative Density: 1.30 x 10³ kg/m³ at 20.0 ±1.0 °C

Water solubility: 8.22 µg/L

Log Pow: 5.00

Vapour pressure: Less than 0.00045 Pa at 25 °C

Granulometry: Proportion of test item having an inhalable particle size <100 µm: 90.8%; less than 10 µm: 2.26%.

Ecotoxicity and Environmental Fate Data

Ready biodegradation: Not readily biodegradable (28 d: 0%) (Aniol, 2012)(OECD TG 301 B)

Absorption/Desorption: logKOC: 3.92, estimated from MCI; logKOC: 3.57, estimated from logKOW

Bioaccumulation in aquatic species: QSAR: LogBCF = 2.62, BCF = 414.2 (BCFBAF model)

Toxicity Data (Human Health)

Acute Toxicity:

- Oral: Rat, LD50 > 2000 mg/kg body weight (Hofmann, Jung, 1988);

- Inhalation: Rat, LC50 > 5 mg/L (OECD 403) (Haferkorn, 2012)

Skin Irritation: No skin irritation (OECD 404) (CiToxLAB Hungary Ltd., 2012)

Eye Irritation: No eye irritation (OECD 405) (CiToxLAB Hungary Ltd., 2012)

Skin Sensitisation: No skin sensitization (OECD 429) (Research Institute for Organic Syntheses Inc., 2012)

Genotoxicity: Negative Ames test (OECD 471) (CiToxLAB Hungary Ltd., 2012); negative in vitro gene mutation HPRT-V79 (OECD 476) (Hargitai, 2012); negative in vitro micronucleus test (OECD 487) (Chladova, 2012)

Repeated dose toxicity, subchronic (OECD 408) (J. Leuschner, 2018): No significant effect was observed during an oral subchronic toxicity study and the NOEL was set to 1000 mg/kg bw/d.

Teratogenicity (OECD 414, B. Hansen): No reproductive effects were seen in an OECD 414 developmental toxicity study when dosed up to 1000 mg/kg bw/d.

 

3. Absorption

The major routes of entry to body for xenobiotics are via the gastrointestinal tract, lungs and the skin (Timbrell, 2000).

3.1 Oral

Transportation of xenobiotics across the GI tract is mainly by passive diffusion (ECHA Chapter R.7c, 2008). That means the GI tract greatly favours the absorption of hydrophobic over non-hydrophobic substances. Grilbond IL-6 is practically insoluble in water and organic solvents. It will not dissolve in the GI fluid well due to its poor solubility in water (ca. 8 µg/L). Furthermore, due to its insolubility and its large molecular weight (476.57 g/mol), it is expected that it will not pass through cell membranes in significant quantities.

The absorption behaviour described above is consistent with the low hazard of Grilbond IL-6 found in acute toxicity studies (LD50 (oral, rat) is greater than 2000 mg/kg body weight) and a subchronic toxicity study (NOEL(rat, p.o.) 1000 mg/kg bw/d). Therefore, a default value of oral absorption is proposed to be 10%.

3.2 Inhalation

The vapour pressure of Grilbond IL-6 is less than 0.00045 Pa at 25 °C, which shows its extremely low volatility and indicates that the inhalation of substance as vapour is very unlikely. However, 90.8% of the particle is smaller than 100 µm, but only 2.26% was below 10 μm. According to the criteria given in the REACH Guidance, particles with aerodynamic diameters below 100 μm have the potential to be inhaled, and therefore the generated dust of the substance may enter into lungs via inhalation if human are expose to dust. On the other hand, considering the molecular weight close to 500, the poor water solubility and the logPow the substance is not preferred for passing the cell membrane. Thus, the absorption rate via inhalation is proposed to be 10%, as the physical accumulation of the dust in lungs cannot excluded for long-term exposure.

In an acute inhalation toxicity study, a 4-hour exposure to Grilbond IL-6 at concentration of 5.07 mg/L air (mass median aerodynamic diameter: 3.579 µm ) revealed slight ataxia, slight tremor, slightly reduced muscle tone and slight dyspnoea immediately, which presumably results from particles in small size (<100 µm) entering the respiratory system. These symptoms can be attributed to physical irritation of the upper respiratory tract. Therefore, a default value of inhalation absorption is proposed to be 10% if direct exposure to the dust cannot be eliminated.

3.3 Dermal

A high LogPow (5.00) indicates that Grilbond IL-6 has a low potential to be absorbed by dermal exposure. There was no skin or eye irritation observed during the test period, which supports the hypothesis above. Furthermore, in a skin sensitisation test (LLNA study) with rats, dosed up to concentration of 50%, Grilbond IL-6 did not lead to irritation and showed no skin sensitisation.

As a result, the skin absorption of the substance is considered to be low and a default value of skin absorption is proposed to be 10%.

 

4. Distribution, Metabolism and Excretion

After poor absorption, the distribution sites of Grilbond IL-6 are limited in the body, presumedly to the liver and kidneys. Phase I metabolism is likely to involve hydrolysis of the substituted urea moieties. Such reactions lead to substances based on caprolactam and hydrolysis products of 4,4-MDI. As phase II metabolism these metabolites can conjugate with glucuronic acid, sulphate, glutathione and other endogenous groups and are then excreted via urine, bile or faeces.

Due to its inertness under physiological conditions, it is believed that limited inhaled Grilbond IL-6 is mainly eliminated in unchanged form through the cilia lung cleaning mechanism. The substance being highly insoluble and having large molecular weight, will hardly enter the body, supposedly by diffusion and endocytosis.

Due to their physicochemical properties and extreme low concentrations it is virtually impossible to extract such metabolites from feces and urine for accurate analysis and assessment. It is therefore technically not feasible to perform a full toxicokinetics assessment.

There is strong evidence that Grilbond IL-6 has low accumulation, based on available toxicity information. There is no treatment-related systemic toxicity and no pathological findings were noted at necropsy in acute oral and inhalation toxicity studies and more relevant in the subchronic oral toxicity study.

 

5. Conclusion

Grilbond IL-6 is expected to be absorbed in humans via different routes – oral (assumed 10%), dermal (assumed 10%) and inhalation route (assumed 10% only if exposed to dusts) due to the high molecular weight, insolubility in water, small particle size and low vapour pressure of the substance. Considering the insolubility, it is concluded that Grilbond IL-6 has very low bioavailability. Distribution of Grilbond IL-6 is expected being limited to liver and kidney. Metabolism involves transformations of the urea carbonyl groups leading to derivatives based on caprolactam and hydrolysed 4,4-MDI which are excreted after conjugation with glucuronic acid, sulphate, glutathione and other endogenous groups via urine or faeces. The available data indicate that Grilbond IL-6 has low toxicity and low accumulation potential.

 

6. Reference

Dr. rer. nat. C. Flügge, MUTAGENICITY STUDY OF GRILBOND IL-6 100% IN MAMMALIAN CELLS (V79) IN THE IN VITRO GENE MUTATION ASSAY (HPRT TEST), report no. 28978, 12-21-2012.

Dr. Hofmann, Dr. Jung, Additol XL 465 Prüfung der akuten oralen Toxizität an der Wistar-Ratte, 12-07-1988.

Dr. rer. nat. J. Haferkorn, ACUTE INHALATION TOXICITY STUDY OF GRILBOND IL-6 100% IN RATS, report no. 28977, 12-12-2012.

ECHA Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (2012), chapter R.7.12 guidance on toxicokinetics.

Judit Hargitai, PhD., The Testing of Grilbond IL-6 100% with Bacterial Reverse Mutation Assay, Study code: 12/342-007M, 11-26-2012.

Magdolna Török-Bathó, M.Sc., Grilbond IL-6 100%: Acute Eye Irritation Study in Rabbits, Study code: 12/342-005N, 12-03-2012.

Magdolna Török-Bathó, M.Sc., Grilbond IL-6 100%: Acute Skin Irritation Study in Rabbits, Study code: 12/342-006N, 12-03-2012.

Petra Plodikova, Dipl.Eng., Grilbond IL-6 100% Skin sensitisation: Local Lymph Node Assay study no. 242/12/6, 11-06-2012.

Renata Chladova, Grilbond IL-6 100%, Micronucleus Test in vitro, ldentification No.: 17/12/C, 12-19-2012.

Timbrell John (2000) Chapter 3, factors affecting toxic responses: disposition. Principles of biochemical toxicology, third edition, page 25.

J. Leuschner, REPEATED DOSE 90-DAY ORAL TOXICITY STUDY OF GRILBOND® IL-6 100% IN RATS - according to OECD guideline 408 and EC method B.26, 2018

B. Hansen, Prenatal developmental toxicity study of Grilbond® IL-6 100% in rats by oral administration, 2018