1-(4-METHOXYPHENYL)-4-(4-NITROPHENYL)PIPERAZINE

Endpoint summary

Description of key information

T001325 (CAS 74852-61-2) is characterised by a moderate molecular weight (313.36 g/mol), a very low water solubility (0.0369 mg/L), a moderate partition coefficient (log Kow 3.4 at pH 7) and a low volatility (vapour pressure of <1.9 E-11 kPa at 25°C).

No or limited dissolution of the substance in the gastrointestinal fluids is expected since it's considered insoluble in water. Based on its lipophilic character, the substance may undergo micellular solubilisation and enter the circulation through the lymphatic systme. The moderate molecular weight favours absorption as well. No systemic nor acute toxicity was observed in a combined 28-day repeated dose toxidity with the reproductive/developmental toxicity screening (OECD 422) and an acute oral toxicity study (OECD 423) respectively. The oral absorption factor of T001325 is therfore set to 50%.

The respiratory absorption factor is set to 100% (conservative approach) due to its lipophilic properties and low water solubility.

The dermal absorption factorfor T001325 is considered 10% based on the fact that the substance is a solid, it's considered insoluble in water and the partition coefficient is moderate. Furthermore, an acute dermal toxicity study (OECD 402) showed no effects related to the test material.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic assessment of T001325

T001325 (CAS 74852-61-2) is a brown odourless powder with a moderate molecular weight (313.36 g/mol), a very low water solubility (0.0369 mg/L), a moderate partition coefficient (log Kow of 3.4 at pH 7) and a low volatility (vapour pressure of <1.9 E-11 kPa at 25°C).

The backbone of T001325 is a piperazine group, with a methoxyphenyl and a nitrophenyl group attached to the 2 nitrogen atoms of the piperazine group. Both the methoxy and nitro group are located at the para position to the piperazine group. T001325 is a nitroaromatic compound which can possibly be recalcitrant against degradation mechanisms (Ju and Parales, 2010). 

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 T001325.

Absorption

Oral/GI absorption:

T001325 is considered insoluble in water. Therefore, no or limited dissolution of the substance into the gastrointestinal fluids is expected leading to low absorption through passive diffusion. However, based on its partition coefficient (log Kow 3.4 at pH 7), the substance is expected to be lipophilic and therefore may undergo micellular solubilisation by bile salts and enter the circulation through the lymphatic system, bypassing the liver. Furthermore, its moderate molecular weight (<500) favours absorption as well.  

In a combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422; van Otterdijk, 2016), T001325 was administered by daily oral gavage to male and female Wistar rats at dose levels of 100, 300 and 1000 mg/kg body weight/day for 29 days (males) or up to 64 days (females). No adverse toxicological effects were observed up to the highest dose tested (1000 mg/kg body weight/day).

An acute oral toxicity study was performed according to the OECD guideline 423 (Latour, 2016) in which T001325 was administered on a single occasion by oral gavage to 2 subsequent groups of 3 female Wistar rats at 2000 mg/kg body weight. Hunched posture, uncoordinated movements and/or piloerection were noted for all animals between days 1 and 3 following test item administration. These signs demonstrated to be reversible; the LD50 was established as greater than 2000 mg/kg. No acute oral toxicity is expected.

Based on the physicochemical properties and the results of the toxicity studies,the oral absorption factor is considered 50%.

 

Respiratory absorption:

Because T001325 has a low volatility, the availability of the powder for inhalation as a vapour is limited. Its mass median aerodynamic diameter could not be determined since the substance is produced as a wet powder (in acetone), so no predictions can be made on the deposition pattern of the particles in the respiratory tract. Based on its low water solubility, the substance is expected to penetrate to the lower respiratory tract, should the substance be inhaled. Furthermore, since the substance is expected to be lipophilic, it can be taken up by micellular solubilisation. No toxicity study with administration via the inhalation route was performed.

Therefore, the respiratory absorption factor is considered 100%.

 

Dermal absorption:

Since T001325 is a solid, the product will not be readily taken up by the skin in comparison to liquid products. The dry product will have to dissolve into the surface moisture of the skin before uptake can take place. In order to cross the skin, the compound must first penetrate into the stratum corneum.

From its partition coefficient (log Kow 3.4 at pH 7), it can be derived that the substance is rather lipophilic enhancing passage across the lipid rich environment of the stratum corneum. However, the substance is not expected to be sufficiently soluble to partition from the stratum corneum into the epidermis based on its very low water solubility (0.0369 mg/L). Therefore, dermal uptake is expected to be minimal.

An acute dermal toxicity study (according to OECD guideline 402; Latour, 2016) where 2000 mg/kg of T001325 was applied to 5 male and 5 female Wistar rats, demonstrated no indications of dermal toxicity, confirming the expectations described above. Furthermore, the substance is demonstrated to not irritate the skin based on a reliablein vivoacute dermal irritation study (equivalent to OECD guideline 404; SafePharm Laboratories Ltd, 2004).

As a result, the dermal absorption factor is considered 10%.

 

Distribution

Based on its lipophilic character, T001325 is expected to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues. 

Accumulation

Since T001325 is lipophilic substance, it will tend to temporary concentrate in adipose tissue. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

Metabolism

Once absorbed, T001325 might undergo phase I biotransformation such as dealkylation, aromatic hydroxylation and nitro reduction followed by conjugation reactions (phase II) such as glucuronidation and sulfation, largely increasing the hydrophilicity.

Excretion

The metabolites of T001325 (such as conjugated glucuronides) will most likely be excreted through the urine. Most of the metabolites will have been filtered out of the blood by the kidneys, though a small amount may enter the urine directly by passive diffusion. Furthermore, T001325 may also be actively secreted through the bile.

 

References

Ju, K. and Parales, R. E. (2010) Nitroaromatic Compounds, from Synthesis to Biodegradation, Mirobiol. Mol. Biol. Rev. 74(2): 250-272.