1-benzhydrylpiperazine

Endpoint summary

Description of key information

Toxicokinetic assessment of T000750

The physicochemical properties of T000750 (CAS 841-77-0) are: a white, slight beige odourless powder, a moderate molecular weight (252.36 g/mol), a particle size of 272.851 µm (Mass Median Aerodynamic Diameter or MMAD), a moderate water solubility (0.476 g/L), a moderate partition coefficient (log Kow of 0.6 at pH 7.1 and 2.5 at pH 12.5) and a low volatility (vapour pressure of <=2.0 E-6 kPa at 25°C). Based on the structure, pKa values, pH in water it is estimated that the product is present in its ionized form for more than 90% at neutral pH.

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

Based on the physicochemical properties (mainly the mass median aerodynamic diameter, see below), the respiratory absorption factor is set to 50%.

The dermal absorption factor for T000750 is set to 50% taking the physicochemical properties and toxicity studies into account.

The description of the assessment can be found under "Additional information"

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

50

Additional information

Toxicokinetic assessment of T000750

T000750 (CAS 841-77-0) is a white, slight beige odourless powder with a moderate molecular weight (252.36 g/mol), a particle size of 272.851 µm (Mass Median Aerodynamic Diameter or MMAD), a moderate water solubility (0.476 g/L), a moderate partition coefficient (log Kow of 0.6 at pH 7.1 and 2.5 at pH 12.5) and a low volatility (vapour pressure of <=2.0 E-6 kPa at 25°C).

The backbone of T000750 is a piperazine group with a diphenylmethylgroup attached to one of the two nitrogen atoms. The presence of nitrogen within the piperazine group can lead to a weak alkaline character, which can be confirmed by the measured pH in water (9.4 - 9.5) and the calculated pKa values based on the Perrin calculation method (8.3 and 8.9). It is estimated that the product is present in its ionized form for more than 90% at neutral pH (Brekelmans, 2017).

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 T000750.

Absorption

Oral/GI absorption:

T000750 is considered favorable for absorption based on its moderate molecular weight (< 500 g/mol), moderate partition coefficient (log Kow between -1 and 4) and a moderate water solubility (0.476 g/L) leading to dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion. Since it is expected that the substance is largely ionized at neutral pH, it is expected that the ionized substance won’t readily diffuse across the biological membranes at the pH levels of the gastrointestinal tract. It is argued that the non-ionised fraction of weak bases is quite lipophilic and therefore easily passes the cell membranes. Due to the increase in pH in the duodenum partly ionized substances are present in an environment where the conditions for absorption are optimal.

A combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422; van Otterdijk, 2017) has been performed by oral gavage with T000750 adminsitered to Wistar Han rats at the dose levels 3, 10 and 30 mg/kg bodyweight/day. A higher motor activity was observed in females dosed at 30 mg/kg bodyweight/day which was considered to be an adverse effect as in could be indicative of neurotoxic potential of the test item, but no treatment-related changes were observed in any of the reproductive parameters investigated in the study. At 30 mg/kg bodyweight/day, none of the females delivered offspring and at 10 mg/kg bodyweight/day, the body weight of the male and female pups were lower compared to the concurrent control group. Therefore, the parental, reproduction and developmental NOAEL (No Observed Adverse Effect Level) values were set to 10, 30 and 3 mg/kg bodyweight/day respectively.

In an acute oral toxicity study (OECD 423; Latour, 2016) in which 2000, 300 and 50 mg/kg bodywheight was applied to Wistar rats by oral gavage, the LD50 value was determined to be in the range of 50-300 mg/kg bodyweight. Based on this observation, T000750 is considered toxic if swallowed.

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

Respiratory absorption:

Given its low volatility, the availability of T000750 for inhalation as a vapour is limited. Based on the fact that its mass mean 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, T000750 can diffuse/dissolve into the mucus lining the respiratory tract, since it is a moderately 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:

T000750 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. Dermal uptake is expected to be low to moderate since the substance is soluble in water to a moderate extent (0.476 g/L) to partition from the stratum corneum into the epidermis. The moderate logKow value of 0.6 at pH 7.1 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 except for local effects (which were considered to not have affected the conclusion of the study) and abnormalities of the epididymides or liver in 2 male animals at macroscopic post mortem examination. Based on an in vivo skin irritation test (4-hour semi-occlusive application) on New Zealand White rabbits (OECD 404; TalviOja, 2007), T000750 was found to be not irritating to skin which implies that no enhanced penetration can be caused by damage to the skin.

As a result, the dermal absorption factor for T000750 is set to 50%.

Distribution

The moderate water solubility and moderate molecular weight predict that T000750 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.

Accumulation

Since T000750 is only slightly lipophilic (log Kow of 0.6), accumulation is considered unlikely.

Metabolism

Based on the structure, T000750 might undergo phase I biotransformation such as hydroxylation and oxidation 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

The most likely route of excretion of T000750 from the systemic circulation is the urine, given its moderate water solubility and molecular weight <300, ionization of the substance at the pH of 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.