4-morpholinopropanesulphonic acid

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert Statement

Adequacy of study:

key study

Study period:

2021-01-14

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Principles of method if other than guideline:

Expert Statement

Details on absorption:

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. In the gastrointestinal tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Therefore, it can be considered as likely that 4-Morpholinepropanesulfonic acid becomes bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is neither confirmed nor rebutted by the results of the acute toxicity study conducted with the test substance, as no mortality or clinical signs have been reported after acute oral administration to rats.


Decomposition of the compound at high temperatures (280 °C) and the low vapor pressure indicate that the substance will not be available for inhalation as a vapor under standard environmental conditions. The substance is a powder and inhalation of dust might occur. Generally, particles with an aerodynamic diameter below 100 µm have the potential to be inhaled, particles below 50 µm may reach the thoracic region and those below 15 µm are able to pass into the alveolar region of the respiratory tract. Since 50 % (by mass) of the particles are in the size range of about 42 µm, a significant amount of the substance is expected to reach the thoracic region upon exposure to dust. Adsorption directly across the respiratory tract epithelium is possible based on the low Pow and good water solubility.

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is above 10 g/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich stratum corneum and dermal uptake will be low. Therefore, for 4-Morpholinepropanesulfonic acid low dermal absorption is predicted because of its high water solubility and the Log Pow of -2.94. As no skin effects were observed in the Guinea pig maximization test with the substance this is neither confirmed nor rebutted.

Details on distribution in tissues:

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, 4-Morpholinepropanesulfonic acid is expected to distribute through-out the body water. Due to its low log Pow the test item is unlikely to bioaccumulate in tissue, and there are no other physicochemical properties indicating bio-accumulating properties.

Details on excretion:

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. Therefore, 4-Morpholinepropanesulfonic acid is expected to be excreted mostly via urine.

Details on metabolites:

Results from the Ames test show that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. Thus, no metabolic activation is expected. Generally it is likely that common protein interaction such as cytochrome P450 oxidases interaction during Phase I metabolism introduce a reactive or polar group in the substance. The oxidation and dehydrogenation are likely first steps of metabolic changes in the morpholine ring, followed by ring-opening. The involvement of cytochrome P450 is also supported by scientific data showing that the morpholine ring, the most defining group of the test substance, can be metabolized by cytochrome P450 starting with the C-N bond cleavage (Combourieu 2000). The resulting compounds might be further processed into polar compounds during the metabolism in Phase II.

Conclusions:

No experimental data on absorption, distribution, metabolism and excretion are available for the substance. This toxicokinetic assessment is based on the physico-chemical properties and existing toxicological data. Based on these, limited oral and dermal absorption are expected. Absorption of dust via inhalation is possible due to particle size of the powder. Metabolism via hydrolysis is not expected. Bioaccumulation of the substance is not expected after repeated exposure. The substance is expected to be predominantly excreted via urine.

Executive summary:

4-Morpholinepropanesulfonic acid is a solid powder with a molecular weight of 209.26 g/mol. The test item has a good water solubility of 597.7 g/L at 20 °C. The log P_ow is estimated to be -2.94 and the vapour pressure is 6.97E-7 Pa at 25 °C. The substance melts under decomposition at 281.6 °C. The median particle size (D50) is 42.54 µm. The substance is not surface active.

No experimental studies on the toxicokinetics of the substance are available. Therefore, an indirect assessment has been conducted based on the physico-chemical and toxicological properties.

Absorption

Oral

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log P_ow values between -1 and 4. In the  gastrointestinal tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Therefore, it can be considered as likely that 4-Morpholinepropanesulfonic acid becomes bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is neither confirmed nor rebutted by the results of the acute toxicity study conducted with the test substance, as no mortality or clinical signs have been reported after acute oral administration to rats.

Inhalative

Decomposition of the compound at high temperatures (280 °C) and the low vapor pressure indicate that the substance will not be available for inhalation as a vapor under standard environmental conditions. The substance is a powder and inhalation of dust might occur. Generally, particles with an aerodynamic diameter below 100 µm have the potential to be inhaled, particles below 50 µm may reach the thoracic region and those below 15 µm are able to pass into the alveolar region of the respiratory tract. Since 50 % (by mass) of the particles are in the size range of about 42 µm, a significant amount of the substance is expected to reach the thoracic region upon exposure to dust. Adsorption directly across the respiratory tract epithelium is possible based on the low P_ow and good water solubility.

Dermal

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log P_ow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is above 10 g/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich stratum corneum and dermal uptake will be low. Therefore, for 4-Morpholinepropanesulfonic acid low dermal absorption is predicted because of its high water solubility and the Log P_ow of -2.94. As no skin effects were observed in the Guinea pig maximization test with the substance this is neither confirmed nor rebutted.

Distribution

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, 4-Morpholinepropanesulfonic acid is expected to distribute through-out the body water. Due to its low log P_ow the test item is unlikely to bioaccumulate in tissue, and there are no other physicochemical properties indicating bio-accumulating properties.

Metabolism

Results from the Ames test show that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. Thus, no metabolic activation is expected. Generally it is likely that common protein interaction such as cytochrome P450 oxidases interaction during Phase I metabolism introduce a reactive or polar group in the substance. The oxidation and dehydrogenation are likely first steps of metabolic changes in the morpholine ring, followed by ring-opening. The involvement of cytochrome P450 is also supported by scientific data showing that the morpholine ring, the most defining group of the test substance, can be metabolized by cytochrome P450 starting with the C-N bond cleavage (Combourieu 2000). The resulting compounds might be further processed into polar compounds during the metabolism in Phase II.

Excretion

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. Therefore, 4-Morpholinepropanesulfonic acid is expected to be excreted mostly via urine.

Summary and conclusion

No experimental data on absorption, distribution, metabolism and excretion are available for the substance. This toxicokinetic assessment is based on the physico-chemical properties and existing toxicological data. Based on these, limited oral and dermal absorption are expected. Absorption of dust via inhalation is possible due to particle size of the powder. Metabolism via hydrolysis is not expected. Bioaccumulation of the substance is not expected after repeated exposure. The substance is expected to be predominantly excreted via urine.

References

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

Combourieu (2000) Combourieu B. et al., Common Degradative Pathways of Morpholine, Thiomorpholine, and Piperidine by Mycobacterium aurum MO1: Evidence from 1H-Nuclear Magnetic Resonance and Ionspray Mass Spectrometry Performed Directly on the Incubation Medium, Appl Environ Microbiol. 2000 Aug; 66(8): 3187–3193., doi: 10.1128/aem.66.8.3187-3193.2000

Frühmesser, A (2018a), Determination of the genotoxic potential of MES hydrate with the In Vitro Mammalian Cell Gene Mutation Test using the Hprt genes following OECD 476, LAUS GmbH, Germany

Frühmesser, A (2018b), Determination of the genotoxic potential of MES hydrate with the "In Vitro Mammalian Cell Micronucleus Test" following OECD 487 and EU B.49, LAUS GmbH, Germany

Hempstock (1997a), MOPS-Na: ACUTE DERMAL IRRITATION TEST IN THE RABBIT, Raschig GmbH,Germany.

Hempstock (1997b), MOPS-Na: ACUTE EYE IRRITATION TEST IN THE RABBIT, Raschig GmbH,Germany.

Paulus, J. (2003), Determination of the mutagenic potential of MOPS HIGH PURITY with the Bacterial Reverse Mutation Test, Raschig GmbH,Germany.

Richeux, F. (2003). Assessment of sensitising properties on albino guinea pigs –Maximisation test according to Magnusson and Kligman – with MOPS, Raschig GmbH, Germany.

Richeux, F. (2005). Assessment of the acute oral toxicity in rats - Acute toxic class Method - with MOPS HIGH PURITY,  Raschig GmbH,Germany.

Szakonyine, I (2019), Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with MES Hydrate in Rats, TOXI-COOP ZRT, Berlini utca 47-49. H-1045 Budapest Hungary

 

Description of key information

No experimental data on absorption, distribution, metabolism and excretion are available for the substance. This toxicokinetic assessment is based on the physico-chemical properties and existing toxicological data. Based on these, limited oral and dermal absorption are expected. Absorption of dust via inhalation is possible due to particle size of the powder. Metabolism via hydrolysis is not expected. Bioaccumulation of the substance is not expected after repeated exposure. The substance is expected to be predominantly excreted via urine (reference 7.1.1-1).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

4-Morpholinepropanesulfonic acid is a solid powder with a molecular weight of 209.26 g/mol. The test item has a good water solubility of 597.7 g/L at 20 °C. The log P_owis estimated to be -2.94 and the vapour pressure is 6.97E-7 Pa at 25 °C. The substance melts under decomposition at 281.6 °C. The median particle size (D50) is 42.54 µm. The substance is not surface active.

Absorption

Oral

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log P_owvalues between -1 and 4. In the  gastrointestinal tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Therefore, it can be considered as likely that 4-Morpholinepropanesulfonic acid becomes bioavailable following the oral route, as indicated by its physicochemical properties. This assumption is neither confirmed nor rebutted by the results of the acute toxicity study conducted with the test substance, as no mortality or clinical signs have been reported after acute oral administration to rats.

Inhalative

Decomposition of the compound at high temperatures (280 °C) and the low vapor pressure indicate that the substance will not be available for inhalation as a vapor under standard environmental conditions. The substance is a powder and inhalation of dust might occur. Generally, particles with an aerodynamic diameter below 100 µm have the potential to be inhaled, particles below 50 µm may reach the thoracic region and those below 15 µm are able to pass into the alveolar region of the respiratory tract. Since 50 % (by mass) of the particles are in the size range of about 42 µm, a significant amount of the substance is expected to reach the thoracic region upon exposure to dust. Adsorption directly across the respiratory tract epithelium is possible based on the low P_owand good water solubility.

Dermal

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log P_owvalues between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is above 10 g/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid richstratum corneumand dermal uptake will be low. Therefore, for 4-Morpholinepropanesulfonic acid low dermal absorption is predicted because of its high water solubility and the Log P_owof -2.94. As no skin effects were observed in the Guinea pig maximization test with the substance this is neither confirmed nor rebutted.

Distribution

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, 4-Morpholinepropanesulfonic acid is expected to distribute through-out the body water. Due to its low log P_owthe test item is unlikely to bioaccumulate in tissue, and there are no other physicochemical properties indicating bio-accumulating properties.

Metabolism

Results from the Ames test show that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. Thus, no metabolic activation is expected. Generally it is likely that common protein interaction such as cytochrome P450 oxidases interaction during Phase I metabolism introduce a reactive or polar group in the substance. The oxidation and dehydrogenation are likely first steps of metabolic changes in the morpholine ring, followed by ring-opening. The involvement of cytochrome P450 is also supported by scientific data showing that the morpholine ring, the most defining group of the test substance, can be metabolized by cytochrome P450 starting with the C-N bond cleavage (Combourieu 2000). The resulting compounds might be further processed into polar compounds during the metabolism in Phase II.

Excretion

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. Therefore, 4-Morpholinepropanesulfonic acid is expected to be excreted mostly via urine.

Summary and conclusion

No experimental data on absorption, distribution, metabolism and excretion are available for the substance. This toxicokinetic assessment is based on the physico-chemical properties and existing toxicological data. Based on these, limited oral and dermal absorption are expected. Absorption of dust via inhalation is possible due to particle size of the powder. Metabolism via hydrolysis is not expected. Bioaccumulation of the substance is not expected after repeated exposure. The substance is expected to be predominantly excreted via urine.

References

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

Combourieu (2000) Combourieu B. et al., Common Degradative Pathways of Morpholine, Thiomorpholine, and Piperidine by Mycobacterium aurum MO1: Evidence from 1H-Nuclear Magnetic Resonance and Ionspray Mass Spectrometry Performed Directly on the Incubation Medium, Appl Environ Microbiol. 2000 Aug; 66(8): 3187–3193., doi: 10.1128/aem.66.8.3187-3193.2000

Frühmesser, A (2018a), Determination of the genotoxic potential of MES hydrate with the In Vitro Mammalian Cell Gene Mutation Test using the Hprt genes following OECD 476, LAUS GmbH, Germany

Frühmesser, A (2018b), Determination of the genotoxic potential of MES hydrate with the "In Vitro Mammalian Cell Micronucleus Test" following OECD 487 and EU B.49, LAUS GmbH, Germany

Hempstock (1997a), MOPS-Na: ACUTE DERMAL IRRITATION TEST IN THE RABBIT, Raschig GmbH,Germany.

Hempstock (1997b), MOPS-Na: ACUTE EYE IRRITATION TEST IN THE RABBIT, Raschig GmbH,Germany.

Paulus, J. (2003), Determination of the mutagenic potential of MOPS HIGH PURITY with the Bacterial Reverse Mutation Test, Raschig GmbH,Germany.

Richeux, F. (2003). Assessment of sensitising properties on albino guinea pigs –

Maximisation test according to Magnusson and Kligman – with MOPS, Raschig GmbH, Germany.

Richeux, F. (2005). Assessment of the acute oral toxicity in rats - Acute toxic class Method - with MOPS HIGH PURITY,  Raschig GmbH,Germany.

Szakonyine, I (2019), Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with MES Hydrate in Rats, TOXI-COOP ZRT, Berlini utca 47-49. H-1045 Budapest Hungary