Morpholinium, 4-[2-[2-[(2-hydroxyphenyl)methylene]hydrazinyl]-2-oxoethyl]-4-methyl-, chloride (1:1)

Endpoint summary

Description of key information

Based on the experimental data of the morpholinium derivate, it is likely that certain amounts become systemically available following oral exposure. Uptake into the systemic circulation following dermal exposure is very limited due to the solid and ionic nature of the test item. Based on the particle size, minor fractions of the morpholinium derivate may be inhaled and can potentially reach the alveolar region, if dust exposure occurs. Based on the molecular structure the substance is assumed to undergo hydrolysis under physiological conditions forming the respective carboxylic acid and hydrazine derivate. Both hydrolysis products might be hydroxylated by P450 enzymes and further conjugated with glucuronic acid. Hydrazines are also known to be N-acetylated. Absorbed morpholinium derivate and its metabolites will be renal excreted due to their high water solubility. Non-absorbed test substance will be readily excreted via the faeces. Neither the morpholinium derivate nor its metabolites have a potential to bioaccumulate within the body.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physico-Chemical Data on 4-[2-[2-[(2-hydroxyphenyl)methylene]hydrazinyl]-2-oxoethyl]-4-methylmorpholinium chloride

 

 4- [2- [2- [(2- hydroxyphenyl) methylene] hydrazinyl]- 2- oxoethyl]- 4-methylmorpholinium chloride appears as a white powder at ambient temperature and pressure. It has a molecular weight (Mw) of 313.783 g/mol. The melting point was determined to be 187 °C at ambient pressure. No boiling point was identified as the substance decomposes before boiling. The morpholinium derivate has a very low vapour pressure (2.5 x 10^-6Pa) which can be regarded as negligible for the present assessment. Particle size measurements determined that approximately 90 % of the crystals are smaller than 996 µm, 50 % are smaller than 44 µm and 10 % are smaller than 16 µm. The substance is very well water soluble as indicated by the measured water solubility value of 181 g/L at 20°C. The LogPow was determined to be < -2.4 at 23°C. The salt dissociates in the respective morpholinium and chloride ion when placed in an aqueous solution. Hydrolysis of the hydrazide bond is expected resulting in the respective carboxylic acid and the hydrazine derivate.

 

2 ADME data on4-[2-[2-[(2-hydroxyphenyl)methylene]hydrazinyl]-2-oxoethyl]-4-methylmorpholinium chloride

 

Absorption

 

Oral route:

Within the gastrointestinal (Gl) tract, the ionic nature, the high water solubility and low LogPow of the morpholinium derivate will limit an uptake into the systemic circulation via passive diffusion. Furthermore, absorption with bulk transport of water is unlikely because of its Mw of greater than 200 g/mol. However, with regard to the hydrolysis products potentially formed in the GI tract absorption through aqueous pores can be assumed due to their lower molecular weights (< 200 g/mol) and high water solubility. The chloride ions will be efficiently absorbed through the walls of the GI tract by active transport processes.

With regards to toxicological data, in an acute oral systemic toxicity study in rats (OECD 423), the LD50 value for themorpholinium derivatewas determined to be about 2000 mg/kg bw. Clinical signs like an impaired general state, piloerection and dyspnoea were observed for the first two hours after test item application. Gross pathology revealed edema and light rose discoloration in all lobes of the lung, dark spotted liver and yellowish discoloration of content in the stomach in some animals.

Furthermore, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (OECD 422) was conducted with the morpholinium derivate. In this study no adverse effects were observed and the NOAEL for general and reproductive toxicity was determined to be 800 mg/kg bw/day. The absolute and relative increase of spleen weight and microscopic alterations in the spleen and sternal bone marrow in females of the 800 mg/kg bw/day group indicate bioavailability of the test item.

Overall, considering the presence of systemic effects in the toxicological investigation at high test substance doses it is likely that limited amounts of the morpholinium derivate reach systemic circulation.

Inhalation route:

Considering the particle size distribution, it cannot be ruled out that minimal fractions of the substance are inhalable if dust exposure occurs. However, based on the hydrophilic properties of the morpholinium derivate it will be retained in the mucus lining the respiratory tract and thus will not be available for systemic absorption.

Dermal route:

As the test item is a solid at room temperature, it has to dissolve into the surface moisture of the skin before any potential uptake can take place. Once dissolved, the ionic nature of the substance will drastically hinder penetration through the skin. Although physicochemical properties of the morpholinium derivate do not favour dermal absorption penetration into the skin cannot be ruled out as indicated by the sensitising effect of the test item. Furthermore, skin irritating properties might enhance dermal absorption due to damage of the skin surface. However, no systemic signs of toxicity were observed in an acute dermal toxicity study and the LD50 was determined to be greater than the limit dose (2000 mg/kg bw).Overall, based on experimental data dermal uptake of the morpholinium derivate cannot be excluded even to very small amounts.

 

Distribution and metabolism

 

Based on the experimental data, it is likely that certain amounts of the morpholinium derivate become systemically available. It is expected to be distributed via the blood stream and was shown to reach the bone marrow as indicated by the findings in the repeated dose toxicity study. However, the test substance did not induce chromosomal damage in this tissue in an in vivo micronucleus assay.

As indicated above the morpholinium derivate is expected to degrade hydrolytically into the respective acetic acid and the hydrazine derivate (Testa B. 2003). Both compounds have a lower molecular weight than the test substance itself and are expected to be well soluble in water. Hydrazine residues are known to undergo Phase I metabolism and to be N-acetylated by N-acetyltransferases (Testa B. 2003). However, hydroxylation of the phenyl residue and conjugation with glucuronic acid or sulphate might be an alternative metabolic pathway of the hydrazine derivate. P450-mediated hydroxylation is also assumed for the morpholinium derivate resulting in a N,N-diacetic acid (Ruina G. et al, 2012).

 

Generally, bioaccumulation within the body tissues is considered unlikely due to the substances’ and metabolites’ physicochemical properties (high water solubility, neg. LogPow value).

Excretion

 

Following oral intake it is expected that the vast majority of the ionised morpholinium derivate will be readily excreted via the faeces.Residual chloride will naturally be excreted with the urine. Absorbed, non-conjugated amountsare ultimately eliminated from the blood via the kidneys and will be excreted with the urine due to their high water solubility. Based on a higher molecular weight biliary excretion cannot be ruled out for metabolites conjugated with glucuronic acid.

 

3 Summary

 

Based on the experimental data of the morpholinium derivate, it is likely that certain amounts become systemically available following oral exposure. Uptake into the systemic circulation following dermal exposure is very limited due to the solid and ionic nature of the test item. Based on the particle size, minor fractions of the morpholinium derivate may be inhaled and can potentially reach the alveolar region, if dust exposure occurs. Based on the molecular structure the substance is assumed to undergo hydrolysis under physiological conditions forming the respective carboxylic acid and hydrazine derivate. Both hydrolysis products might be hydroxylated by P450 enzymes and further conjugated with glucuronic acid. Hydrazines are also known to be N-acetylated. Absorbed morpholinium derivate and its metabolites will be renal excreted due to their high water solubility. Non-absorbed test substance will be readily excreted via the faeces. Neither the morpholinium derivate nor its metabolites have a potential to bioaccumulate within the body.

4 References

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press,,, 2nd Edition 688-689.

 

Ruina G., Liang L., Cen X., Xingxing D., Dafang Z., and Xiaoyan C. (2012)Metabolism and Pharmacokinetics of Morinidazole in Humans: Identification of Diastereoisomeric Morpholine N+-Glucuronides Catalyzed by UDP Glucuronosyltransferase 1A9,Drug Metabolism And Disposition 40:556–567.

 

Testa B., Mayer JM (2003) Hydrolysis in Drug and Prodrug Metabolism.VHCA, Zürich, Switzerland, Wiley-VCH, Weinheim, Germany.