4-(2-hydroxyethyl)piperazin-1-ylethanesulphonic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

In general, the molecular weight of 238 g/mol of the test item is favouring absorption. As a zwitterion it contains ionisable groups. It is generally thought that ionized substances do not readily diffuse across biological membranes. Furthermore, the hydrophilicity of the test item as determined by its high water solubility and low octanol/water partition coefficient indicate a low potential for passive diffusion through cell membranes. The absence of any acute and sub-acute toxic effects following oral application also supports the hypothesis of low oral and GI absorption.
Due to the low vapour pressure, inhalation of the test item as a vapour is considered negligible. However, partciles of the test item are likely to be inhaled. It can be expected that about 10% of inhaled particles can reach the alveolar region of the respiratory tract. Its hydrophilicity indicates a low potential for passive diffusion and micellular solubilisation.
Being a solid, the test item will have to dissolve into the surface moisture of the skin before uptake can begin. Due to its hydrophilicity (water solubility >> 10000 mg/l and log P << 0) it is very unlikely to cross he lipid rich environment of the stratum corneum. The test item has no other properties, such as being surface active, being a skin irritant or an acutely dermal toxicant, favouring dermal uptake. Therefore, dermal uptake can be expected to be low.

Details on distribution in tissues:

The rate at which the highly water soluble test item will distribute can be assumed to be limited by the rate at which they cross cell membranes and access to the central nervous system (CNS) or testes is likely to be restricted by the blood-brain and blood-testes barriers. Since the substance is very hydrophilic, has a low log P, and is ionisable, accumulation in the lung, adipose tissue and stratum corneum is not expected.

Details on excretion:

As the test item has a molecular weight < 300 g/mol and is very well water soluble, excretion via urine can be assumed. All other excretion routes such as exhalation, bile, breast milk and salvia/sweat are very unlikely due to its low vapour pressure and hydrophilicity.

Metabolite characterisation studies

Metabolites identified:

not specified

Applicant's summary and conclusion

Executive summary:

No study is available, in which the toxicokinetic properties (distribution, metabolism, elimination) of the test item were investigated.

The expected toxicokinetic behaviour is assessed in a qualitative manner based on the physicochemical properties and the results from the available toxicological studies following the instructions given in the ‘Guidance on information requirements and chemical safety assessment - Chapter R.7c: Endpoint specific guidance’ (Version 1.1).

Physico-chemical data

The test item is a zwitterionic organic chemical. It is a white crystalline powder with a molecular weight of 238.31 g/mol. It has a median particle size of 74 μm with a 10%-quantile of 14.3 μm. The test item is highly water soluble (703.6 g/L at 20 °C) and is considered to be hydrolytically stable as it does not hydrolyse at pH 4, 7 and 9 (at 50 °C). With an estimated log P of < -3.85, the test item is hydrophilic. It has a very low volatility, as its vapour pressure was estimated to be 3.2*10-8 Pa at 25 °C. With a mean surface tension of 63.98 mN/m (at 20°C), the test item is not surface active.

Toxicological data

The test item has been demonstrated to be not acutely toxic via the oral and the dermal route. With the exception of reduced body weight gain when applied dermally, no adverse effects were observed.

It did not induce any skin reactions in rabbits, such as erythema or edema, when tested for its skin irritation/corrosion potential.

The instillation of the test item into rabbit eyes resulted in conjunctiva redness and discharge. These effects were considered as slight transient signs of mechanical irritation. All effects were reversible after 48h after application. Consequently, the test item is not classified for eye irritating effects.

The test item did not induce any effects in a guinea pig test for skin sensitisation.

The sub-acute toxicity of the test item was investigated in 28-day study. When administered by gavage to Sprague-Dawley rats at the dose-levels of 100, 300 or 1000 mg/kg/day, it was clinically well tolerated. No overt signs of toxicity were observed in hematological, blood biochemical or urinalysis parameters. Organ weights were un-affected by treatment and no macroscopic or histopathological findings revealed a treatment-related effect.

Consequently, a No Observed Effect Level (NOEL) of 1000 mg/kg/day was established.

As the test item did not induce chromosome aberrations in cultured human lymphocytes, it was concluded to be negative in the L5178Y/TK+/- Mouse Lymphoma assay and was not mutagenic in a Salmonella typhimurium reverse mutation (Ames) assay with and without metabolic activation. Consequently, it is considered to be not mutagenic.

The prenatal developmental toxicity of the test item by the oral route was evaluated in rats. When administered by gavage to Sprague-Dawley rats at the dose-levels of 100, 300 or 1000 mg/kg/day from gestation day 6 to 19, the test item was well tolerated by the dams (no clinical signs and no adverse macroscopic post-mortem findings) confirming the results of the 28-day study. Litter data (pre- and post-implantation, number of life fetuses and fetal body weight) as well as fetal observations (external, visceral, cartilage and skeletal examinations) were not affected by treatment.

Oral and gastro-intestinal (GI) absorption

In general, the test item’s molecular weight of 238 g/mol is favouring absorption. As a zwitterion. it contains ionisable groups. It is generally thought that ionized substances do not readily diffuse across biological membranes. Furthermore, the hydrophilicity of the test item as determined by its high water solubility and low octanol/water partition coefficient indicate a low potential for passive diffusion through cell membranes. The absence of any acute and sub-acute toxic effects following oral application also supports the hypothesis of low oral and GI absorption. Therefore, 10% absorption as worst case value is assumed.

Inhalative absorption

Due to the low vapour pressure, inhalation of the test item as a vapour is considered negligible. However, the test item particles are likely to be inhaled. It can be expected that about 10% of inhaled particles can reach the alveolar region of the respiratory tract. Its hydrophilicity indicates a low potential for passive diffusion and micellular solubilisation.

Dermal absorption

Being a solid, the test item will have to dissolve into the surface moisture of the skin before uptake can begin. Due to its hydrophilicity (water solubility >> 10000 mg/l and log P << 0) it is very unlikely to cross he lipid rich environment of the stratum corneum. The test item has no other properties, such as being surface active, being a skin irritant or an acutely dermal toxicant, favouring dermal uptake. Therefore, dermal uptake can be expected to very low, if not negligible, and a worst case absorption rate of 10% is assumed for risk assessment.

Distribution

The rate at which the highly water soluble test item will distribute can be assumed to be limited by the rate at which they cross cell membranes and access to the central nervous system (CNS) or testes is likely to be restricted by the blood-brain and blood-testes barriers. Since the substance is very hydrophilic, has a low log P, and is ionisable, accumulation in the lung, adipose tissue and stratum corneum is not expected.

Metabolism

The available information does not allow any conclusion on the metabolism of the test item.

Reactivity

Available studies on genotoxicity of the test item were negative, i. e. there is no indication for reactivity of the test item.

Excretion

As the test item has a molecular weight < 300 g/mol and is very well water soluble, excretion via urine can be assumed. All other excretion routes such as exhalation, bile, breast milk and salvia/sweat are very unlikely due to the test item's low vapour pressure and hydrophilicity.