1-acetyl-4-(4-hydroxyphenyl)piperazine

Endpoint summary

Description of key information

Toxicokinetic assessment of T001141

T001141 (CAS 67914-60-7) is a white, beige odourless powder with a moderate molecular weight (220.27 g/mol), a particle size of 597.669 µm (Mass Median Aerodynamic Diameter or MMAD), a high water solubility (3.35 g/L), a moderate partition coefficient (log Kow <0.3) and a low volatility (vapour pressure of <2.1 E-11 kPa at 25°C).

The structure and pKa values indicate that the product is not ionized at neutral pH. Based on the physicochemical data and toxicity studies, the oral absorption factor is set to 100%, and the dermal absorption factor is set to 50%. The respiratory absorption factor is set to 50% based on the physicochemical properties.

The assessment is described in the section underneath ("Additional information").

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

50

Additional information

Toxicokinetic assessment of T001141

T001141 (CAS 67914-60-7) is a white, beige odourless powder with a moderate molecular weight (220.27 g/mol), a particle size of 597.669 µm (Mass Median Aerodynamic Diameter or MMAD), a high water solubility (3.35 g/L), a moderate partition coefficient (log Kow <0.3) and a low volatility (vapour pressure of <2.1 E-11 kPa at 25°C).

The backbone of T001141 is a piperazine group, with a methoxygroup and a hydroxyphenylgroup attached to the first and second nitrogen respectively. The presence of nitrogen within the piperazine group can lead to a weak alkaline character, while the phenol group has a weak acidic character which can be confirmed by the calculated pKa values based on the Perrin calculation method (Reingruber, 2017). Therefore, it is estimated that the product is not ionized at neutral pH.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of T001141.

Absorption

Oral/GI absorption:

T001141 is considered favorable for absorption since it has a moderate molecular weight (< 500 g/mol), a moderate log Kow value (between -1 and 4) and a high water solubility (3.35 g/L) leading to dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine. Based on the calculated pKa values, no ionization of T001141 is expected in the relevant pH range.

A combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422; Peter, 2017) has been performed by oral gavage with T001141 on Wistar Han rats at the dose levels 0, 50, 150 and 500 mg/kg bodyweight/day. Significant general toxicity was observed in males and females treated at 500 mg/kg/day such as clinical signs of toxicity, reduced body weight gain and food consumption, adverse morphological changes in the spleen with associated changes in blood parameters, decreased number of circulating total white blood cells and adverse morphological changes in the thyroid gland and bone marrow in both sexes and adverse morphological findings in the thymus, testes and epididymides in males only.

At a dosage of 500 mg/kg/day, there were no females with live offspring. No abnormalities were observed in the reproductive organs of femals treated with 500 mg/kg/day, this observation was attributed to the severe effects observed on the testes (abnormal spermatogenesis). No test-item related reproduction toxicity and no developmental toxicity was observed at 50 and 150 g/kg/day. Possible developmental toxicity at 500 mg/kg/day could not be evaluated because none of the two pregnant females treated at 500 mg/kg/day had offspring. The parental, reproduction and developmental NOAEL (No Observed Adverse Effect Level) were set to 150 mg/kg/day.

From an acute oral toxicity study (OECD 423; Latour, 2016) in which 2000 mg/kg body weight and 300 mg/kg bodywheight was applied to Wistar rats, it could be derived that the LD50 was in the range of 300 – 2000 mg/kg bodyweight, with a cut-off value of 2000 mg/kg bodyweight. Based on this observation, T001141 is considered harmful if swallowed.

Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is set to 100%.

Respiratory absorption:

Given its low volatility, the availability of T001141 for inhalation as a vapour is limited. Based on the fact that its aerodynamic diameter is larger than 100 µm, the solid particles have no or very limited potential to be inhaled (no presence of inhalable or respirable particles).

Based on the other physicochemical properties, T001141 can diffuse/dissolve into the mucus lining the respiratory tract, since it is a highly water soluble powder. Its slightly lipophilic character (logKow>0) implies that the product has the potential to be subsequently absorbed directly across the respiratory tract epithelium through passive diffusion. The portion of the product which is not dissolved into the mucus could be coughed or sneezed out of the body or swallowed. As described above, the product has the potential to be absorbed after oral intake. However, based on the fact that the mass median aerodynamic diameter is so high, little respiratory absorption is expected (as described above).

Therefore, the respiratory absorption factor is set to 50%.

Dermal absorption:

T001141 is a solid substance and therefore not readily taken up by the skin in comparison to liquid products. The product will have to dissolve into the surface moisture of the skin before uptake can take place. Based on its high water solubility (3.35 g/L), dermal uptake is expected to be moderate to high since the substance is sufficiently soluble in water to partition from the stratum corneum into the epidermis. The moderate logKow value of <0.3 indicates that the substance is slightly lipophilic and therefore easily crosses the lipid rich environment of the stratum corneum leading to dermal uptake.

An acute dermal toxicity study (OECD 402; Latour, 2016) with Wistar rats to which a single dose of 2000 mg/kg was applied, showed no effects related to the test material. Based on anin vivoskin irritation test on New Zealand White rabbits (OECD 404; SafePharm Laboratories Ltd., 2004). T001141 was found to be a mild irritant and should not be classified as irritant (mean score was below the cut-off value) which implies that no enhanced penetration can be caused by damage to the skin.

As a result, the dermal absorption factor for T001141 is set to 50%.

Distribution

The high water solubility and moderate molecular weight predict that T001141 will probably distribute through the body due to diffusion through aqueous channels and pores. Since the substance is slightly lipophilic (logKow>0), the substance is likely to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues. The conclusions of the oral toxicity study indicate that the target organs are mainly the thyroid gland and spleen (andin the thymus, testes and epididymides in males only).

Accumulation

Since T001141 is only slightly lipophilic (log Kow <0.3), accumulation is considered unlikely.

Metabolism

Based on the structure, T001141 might undergo phase I biotransformation such as oxidation and reduction followed by conjugation reactions (phase II) such as glucuronidation (by the enzyme glucuronosyltransferase) and sulfation (by the enzyme sulfotransferase. The Phase II conjugation reactions largely increase the hydrophilic character of the product. Metabolism mainly takes place in the liver, causing route specific presystemic (or first pass) effects, especially after oral intake. Other metabolic changes may take place in the gastrointestinal (GI) flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

Excretion

Given its high water solubility and molecular weight <300, the most likely route of excretion of T001141 from the systemic circulation is the urine. In general, conjugated metabolites such as glucuronides and sulfates from Phase II biotransformation reactions are excreted in the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium. Another route of excretion of conjugated derivatives (such as glucuronides) is the bile. The excretion via the bile is highly influenced by hepatic function since metabolites formed in the liver may be excreted directly into the bile without entering the bloodstream. Products in the bile pass through the intestine before excretion in the faeces and can thus undergo enterohepatic recycling which will prolong their half-life. Furthermore, T001141 can be excreted in the saliva (where in can be swallowed again) or in the sweat since it is non-ionized and slightly lipid soluble.