N-(2-(4-amino-N-ethyl-m-toluidino)ethyl)methanesulphonamide sesquisulphate

Endpoint summary

Description of key information

Oral absorption is likely for Methanesulfonamide, N-[2-[(4-amino-3-methylphenyl)ethylamino]ethyl]-, sulfate (2:3) (CAS 25646-71-3) and absorption via inhalation route cannot be excluded. Dermal absorption is expected to be very low. As the parental molecule is expected to be metabolized by enzymatic activities in the gastrointestinal tract, the metabolites will probably be distributed in the body, most likely in the water compartment of the body. The substance is not considered to accumulate. Excretion is expected to be predominantly via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Methanesulfonamide, N-[2-[(4-amino-3-methylphenyl)ethylamino]ethyl]-, sulfate (2:3) (CAS 25646-71-3) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and the guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of Methanesulfonamide, N-[2-[(4-amino-3-methylphenyl)ethylamino]ethyl]-, sulfate (2:3) (CAS 25646-71-3) is 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 guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017).

 

Methanesulfonamide, N-[2-[(4-amino-3-methylphenyl)ethylamino]ethyl]-, sulfate (2:3) (CAS 25646-71-3) is a solid substance with a molecular weight (MW) of 836.99 g/mol. The substance has a very high water solubility of > 1000 g/L at 20 ºC (Ciric, 2018) and the log Pow is <-5.1 at 19.9 °C. The substance has a low vapour pressure of 0.022 Pa at 20 °C and the determination of the particle size revealed an MMAD of 542.128 µm and d10 of 156.275 µm (Ciric, 2018).

In aqueous solution the sulfate portion would be completely dissociated, leaving the cation species (MW 274.4 g/mol) to be in equilibrium with the neutral species (MW 271.38 g/mol) of Methanesulfonamide, N- 2- (4-amino-3-methylphenyl)ethylamino ethyl. Therefore a molecular weight of 271 g/mol for Methanesulfonamide, N- 2- (4-amino-3-methylphenyl)ethylamino ethyl and 96 g/mol for sulfate were considered relevant for assessment of toxicokinetic behaviour. 

Absorption

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).

 

Oral

Regarding oral/gastro-intestinal (GI) absorption, molecular weights below 500 are favourable for absorption, whereas molecular weights above 1000 do not favour absorption. Generally the smaller the molecule the more easily it may be taken up.

Upon oral uptake, the substance will readily dissolve into the gastrointestinal fluids. This change will alter the physico-chemical characteristics of the substance and hence predictions based upon the physico-chemical characeteristics of the parent subtstance do not longer apply. Considering the molecular weight of dissociation products, absorption after oral administration is favourable. 

Acute oral toxicity data resulted in death of rats at a dose of 300 mg/kg bw/day and above, a definite LD50 value was not determined (Key, NBR, rat, 1982). In this non-GLP study groups of four male rats were administered the test material at oral doses of 75, 300, or 1200 mg/kg bw via gavage. No mortality occurred in animals dosed with 75 mg/kg bw; however, in both the 300 and 1200 mg/kg bw dose groups, 3 out of 4 animals died. Piloerection was observed in all treated animals. Animals dosed with 300 or 1200 mg/kg bw also exhibited the following clinical signs of toxicity: convulsion, cyanosis, respiratory depression, lacrimation, salvation, hunched posture, and hypothermia, respiratory paralysis. Decreased body weight, as well as decreased food and water consumption, also were observed at 300 and 1200 mg/kg bw. In those animals that were found dead, atrophy of the stomach and exfoliation of gastric mucosa were noted. In summary, the LD50 was established at 75 mg/kg bw > LD50 < 300 mg/kg bw. These findings of the acute oral toxicity study are indicative of systemic toxicity.

In a range finding study for an OECD 422 test, rats received 75 and 150 mg/kg bw by daily oral gavage up to 10 days. At 150 mg/kg bw, all females were sacrificed in extremis on Day 3. At 75 mg/kg bw, various clinical signs were noted, at necropsy, one female showed several gray-white foci on the heart with slight weight loss, and mean liver and kidney weight was increased. In the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422), rats were exposed to the test substance at dose levels of 5, 15 and 50 mg/kg bw/day by oral gavage. Blue discolouration of the urine was recorded for most mid and high dose females during the last week of their scheduled treatment period. This finding occurred in the absence of adverse renal pathology. It is conceivable that the bluish discolouration had occurred due to presence of the test item and/or its metabolite(s) in the urine resulting in a specific light diffraction.

 If signs of systemic toxicity are present, then absorption has occurred (ECHA, 2017).

Overall, taking into account the molecular weight and the available toxicological data of Methanesulfonamide, N-[2-[(4-amino-3-methylphenyl)ethylamino]ethyl]-, sulfate (2:3) (CAS 25646-71-3) indicating systemic toxicity, the potential for oral absorption of the substance is high.

 

Dermal

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. 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.Moreover, a log Pow between 1 and 4 and low molecular weights (< 100) are favourable for dermal absorption. Furthermore, if a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. Also if a substance is identified as skin sensitizer some dermal uptake must have occurred (provided the challenge application was to intact skin) although it may only have been a small fraction of the applied dose (ECHA, 2017). The molecular weight of the test substance is > 500 and thus may be too large for dermal uptake. Moreover, since the water solubility is above 10 g/L and the log Pow value is below 0, the substance will be too hydrophilic to cross the lipid rich environment of the stratum corneum.

However after dissociation in aqueous solution, dermal uptake might be possible.

QSARbased dermal permeability regarding a molecular weight of 837.0 g/mol, a log Pow of -5.1 and a water solubility of >1000 g/L, calculated a permeability constant (Kp) of 1.4E-11 cm/h and a low dermal absorption of 0.00001 µg/cm²/h (DERMWIN v2.02). This value is considered as indicator for a very low dermal absorption of 1% (very low).

A GLP compliant acute dermal toxicity study was conducted with the test substance, N-(2 -(4 -Amino-N-ethyl-m-toluidino)ethyl)methanesulphonamide sesquisulphate, which was conducted according to OECD TG 402 (Shepard, 1997). In this study groups of 5 male and 5 female Sprague-Dawley strain rats were administered the test substance at a dose of 2000 mg/kg bw dermally (solid, moistened with water) (Shepard 1997). The animals were observed for 14 days for mortality, clinical signs of toxicity and body weight change after administration. No mortality occurred at a dose of 2000 mg/kg bw.The only treatment-related changes seen at necropsy were limited to discoloration (black) of the hair adjacent to the application site of all animals. The LD50 for males and females was established at > 2000 mg/kg bw. Since, the substance did not induce signs of systemic toxicity at doses up to 2000 mg/kg bw, it can be assumed that no significant dermal absorption has occured. Furthermore, a GLP compliant, reliable skin irritation study (according to OECD 404) was performed in rabbits with N-(2-(4-Amino-N-ethyl-m-toluidino)ethyl)methanesulphonamide sesquisulphate using water as vehicle (Shepard, 1997). Skin reactions were evaluated according to the Draize scoring system 1, 24, 48 and 72 h post-application. No symptoms of systemic toxicity were observed in any animal during the test period and no mortality occurred during the course of the study. Mean erythema and oedema scores for the 72 hour observation period were 0, respectively. Since, the substance did not show skin damaging properties, enhancement of skin penetration is not likely to occur. The tested substance was a sensitizer in a non-GLP study in guinea pigs, which was similar to OECD 406 (Linden and Boman, 1988), this allows the assumption that at least a small fraction of the dose was absorbed. Based on the available acute dermal toxicity and skin irritation data, it can be anticipated that the dermal absorption is low.

Overall, taking into account the physico-chemical properties and the available toxicological data of Methanesulfonamide, N-[2-[(4-amino-3-methylphenyl)ethylamino]ethyl]-, sulfate (2:3) (CAS 25646-71-3), the potential for dermal absorption of the substance is very low.

 

Inhalation

The vapour pressure indicates if a substance may be available for inhalation as a vapour. As a general guide, highly volatile substances are those with a vapour pressure greater than 25 kPa. Substances with low volatility have a vapour pressure of less than 0.5 kPa (or a boiling point above 150 °C) (ECHA, 2017). Substances that can be inhaled include gases, vapours, liquid aerosols (both liquid substances and solid substances in solution) and finely divided powders/dusts. Substances may be absorbed directly from the respiratory tract or, through the action of clearance mechanisms, may be transported out of the respiratory tract and swallowed. This means that absorption from the GI tract will contribute to the total systemic burden of substances that are inhaled.

The substance has a very low vapour pressure of 0.022 Pa at 20 °C. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be considered negligible. However, it is known that the test substance is a powder. Precise deposition patterns for dusts will depend not only on the particle size of the dust but also the hygroscopicity, electrostatic properties and shape of the particles and the respiratory dynamics of the individual. As a rough guide, particles with aerodynamic diameters below 100 μm have the potential to be inspired. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA 2017). Granulometry data of the test substance indicate, that less than 10% of the test sample's mass is comprised of smaller particles than 156.275 µm, indicating a low potential to be inspired. However if inspired, the solid substance would readily dissolve into the mucus lining of the respiratory tract. In general, then very hydrophilic substances might be absorbed through aqueous pores (for substances with molecular weights below around 200) or be retained in the mucus and transported out of the respiratory tract.

Systemic toxicity was observed after oral uptake. This indicates the potential for absorption following ingestion and it is therefore likely that the substance will also be absorbed to some extent after inhalation via clearance mechanisms (ECHA 2017). 

In conclusion, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour or dust can be considered negligible. However, if the substance is inhaled, it is likely that the substance will also be absorbed.

 

Distribution and accumulation

Distribution of a compound within the body depends on the rates of the absorption and the physico-chemical 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 (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Basis for distribution is that the substance is absorbed.

The acute oral toxicity study and the range-finding study of the OECD 422 test indicates systemic toxicity; therefore it can be assumed that absorption has occurred and that it is likely that the dissociation products of Methanesulfonamide, N-[2-[(4-amino-3-methylphenyl)ethylamino]ethyl]-, sulfate (2:3) (CAS 25646-71-3) or its metabolites will enter the blood circulating system through which they will be distributed within the body.

Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops the substance will be gradually eliminated at a rate dependent on the half-life of the substance. 

Metabolism

No experimental data on the metabolism of N-(2-(4-amino-N-ethyl-m-toluidino)ethyl)methanesulphonamide sesquisulphate were available.

Metabolism of the substance was assessed using the QSAR OECD toolbox v4.2 (OECD, 2018). The toolbox did not provide any data on observed metabolism. Thus using metabolism simulator functions, the toolbox predicted 6 skin metabolites, 20 rat liver S9 metabolites, 13 in vivo rat metabolites, and 38 microbial metabolites.

 

For skin metabolism the predicted metabolites were: acetic acid, acetaldehyde, N-{2-[(E)-(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)amino]ethyl}methanesulfonamide, N-[2-(4-amino-3-methylanilino)ethyl]methanesulfonamide, N-(2-{[4-amino-3-(hydroxymethyl)phenyl](ethyl)amino}ethyl)methanesulfonamide, and (1E)-N-ethyl-4-imino-N-{2-[(methanesulfonyl)amino]ethyl}-3-methylcyclohexa-2,5-dien-1-iminium.

 

For in vivo rat metabolism the predicted metabolites were: Acetic acid, Acetaldehyde, 2,5-Diaminotoluene, N-(4-amino-3-methylphenyl)glycine, (4-amino-3-methylanilino)acetaldehyde, N-[2-(4-amino-3-methylanilino)ethyl]methanesulfonamide,  N-(4-amino-3-methylphenyl)-N-ethylglycine, [(4-amino-3-methylphenyl)(ethyl)amino]acetaldehyde, N-{2-[(4-amino-3-hydroxy-5-methylphenyl)(ethyl)amino]ethyl}methanesulfonamide, N4-Ethyl-2-methyl-1,4-benzenediamine, N-(Methylsulfonyl)glycine, N-(2-Oxoethyl)methanesulfonamide, and Methanesulfonamide.

 

Microbial metabolites comprised amongst others (2e)-4,6-dioxo-2-heptenoic acid, acetone, acetic acid, acetaldehyde, 4-hydroxy-6-methylaniline,ethanimine, 1,4-benzenediamine, n4-ethyl-2-methyl-, n-ethylglycine, n-ethylethylenediamine, methanol, n-(methylsulfonyl)glycine, n-(2-oxoethyl)methanesulfonamide, methanesulfonamide, methanesulfonic acid, oxalic acid, fumaric acid, and glyoxylic acid.

 

The major pathways of the parental substance are unknown, therefore no final conclusion can be drawn on the metabolism in mammalian organisms.

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the compound finally excreted may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product as compared to the parent. Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. In contrast, molecules that are excreted in the bile have a high molecular weight (ECHA, 2017). The molecular weight of the parent substance in solution is <300, indicating that urinary excretion of the parent substance is likely Renal excretion of the substance is supported by the findings in the OECD 422 study. Blue discolouration of the urine was recorded for most females dosed at 15 and 50 mg/kg bw/day during the last week of their scheduled treatment period. It is conceivable that the bluish discolouration had occurred due to presence of the test substance and/or its metabolite(s) in the urine resulting in a specific light diffraction. Thus the test substance is expected to be excreted predominantly via the urine. 

 

References

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

 

OECD (2018). (Q)SAR Toolbox v4.2 Developed by Laboratory of Mathematical Chemistry, Burgas, Bulgaria, for the Organisation for Economic Co-operation and Development (OECD).Calculation performed 24 April 2018.http://toolbox.oasis-lmc.org/?section=overview