2,2'-[(4-methylphenyl)imino]bisethanol

Endpoint summary

Description of key information

Oral and dermal absorption potential is considered to be likely for N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1), whereas an inhalation absorption potential is assumed to be negligible. N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) is expected to be distributed within the body and excreted via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 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), assessment of the toxicokinetic behaviour of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) 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).

N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) is a solid at 20°C which has a molecular weight of 195.3 g/mol and a water solubility of 19.8 ± 0.23 g/L. The log Pow value is 2.0 and the vapour pressure is 4.47 x 10E-4 Pa.

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

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, but 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) as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2017).

The high water solubility (19.8 ± 0.23 g/L) and the low log Pow value of 2.0 of the compound indicate that absorption is likely by the ability to dissolve into GI fluids. Thus, in consideration of the molecular weight of 195.3 g/mol absorption following oral administration is favourable.

Studies on acute oral toxicity of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) showed signs of systemic toxicity and mortality resulting in a LD50 value of 959 mg/kg bw in rats and a LD100 value of 50 mL/kg bw in cats (Bayer AG, 1981; Bayer AG, 1985).

Overall, taking into account the physico-chemical properties and the available toxicological data the oral absorption potential of the registered substance is anticipated to be high.

 

Dermal

There are no data available on dermal absorption of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1). On the basis of the following considerations, the dermal absorption of the substance is considered to be high.

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Thus, with a high water solubility of 19.8 g/L, dermal uptake of the substance is likely to be high. In addition, log Pow values between 1 and 4 favour dermal absorption particularly if water solubility is high (ECHA, 2017).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

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

The Kp was calculated for N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) (please refer to Table 1). QSAR calculations confirmed this assumption, as dermal flux rates ranging of 0.013 mg/cm2 per h was calculated indicating high dermal absorption potential for the compound (please refer to Table 1, Dermwin v2.02, EpiSuite 4.1).

Table 1: Dermal absorption value for N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) (calculated with Dermwin v 2.02, Epiweb 4.1)

Component	Structural formula	Flux (mg/cm2/h)
N,N-Dihydroxyethyl-p-toluidine	C11 H17 N1 O2	0.013

Overall, taking into account the physico-chemical properties of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) and the QSAR calculations, the dermal absorption potential of the substance is anticipated to be high.

Inhalation

Inhalation of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) is considered negligible since the test substance is marketed or used in a non solid or granular form. Moreover, inhalation of the test substance is unlikely with regard to the vapour pressure (4.47E-04 Pa), which indicates a low inhalation potential thus being of low volatility (ECHA, 2017). 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.

Based on the physical state and the physico-chemical properties of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1), absorption via the lung is expected as negligible.

Distribution and accumulation

No data were found regarding the distribution. 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. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution (ECHA, 2017).

Thus, due to the small molecular weight (195.3 g/mol) and the hydrophilic character distribution within the body is possible. However, a bioaccumulation potential of N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) is not assumed due to the hydrophilic character.

Metabolism

No data are available regarding metabolism. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.1, OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 14 hepatic and 5 dermal metabolites were predicted for the test substance, respectively. Primarily, hydroxylation of the methyl group and oxidation to the aldehyde or carboxy function is predicted in the liver. Besides these reactions, cleavage of the alcoholic side chain followed by a further hydroxylation and/or oxidation may occur in the liver. In the skin, hydroxylation of the methyl group is predicted. These predicted metabolites can be regarded as phase I metabolites which are a common prerequisite for the phase II reactions or conjugation reactions, which transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic. Phase II metabolism by e.g. uridine 5′-diphospho (UDP)-glucuronosyltransferases and sulfotransferases typically generates excretable hydrophilic metabolites by transferring activated glucuronic acid and sulfate-moiety to hydroxyl groups of the substrate, respectively (Aktories, 2005). Up to 28 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Regarding the available data on genetic toxicity, no evidence for a mutagenic potential in bacterial cells from the registered substance in the absence and in the presence of a metabolic activation system was observed, respectively.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa).Only limited conclusions on excretion of a compound can be drawn based on physicochemical data.Low molecular weight (below 300 g/mol in rat), good water solubility, and ionization of the molecule at the pH of urine are characteristics favourable for urinary excretion.Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. Thus, based on the available data no final conclusion on the excretion route is possible.

References

Aktories K., Förstermann U., Hofmann F. and Starke K. (2005): Allgemeine und spezielle Pharmakologie und Toxikologie. 9. Auflage, Urban & Fischer Verlag

Aungst B. and Shen D.D. (1986): Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

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