2-(4-tert-butylphenyl)-6-cyano-5-[bis(ethoxycarbonylmethyl)carbamoyloxy]-1H-pyrrolo[1,2-b][1,2,4] triazole-7-carboxylic acid 2,6-di-tert-butyl-4-methylcyclohexylester

Endpoint summary

Description of key information

No studies are available. The molecular structure, molecular weight, physico-chemical properties incl. water solubility and octanol-water partition coefficient ofUC-141 do not favour oral, inhalative and dermal absorption. Distribution might occur to a certain extent. UC-141 has a low bioaccumulation potential, because in case of absorption UC-141 will be metabolized in the liver and rapidly be excreted via bile and/or urine. The unabsorbed fraction will be excreted via faeces. 

Additional information

There were no studies available in which the toxicokinetic properties of 2-(4-tert-butylphenyl)-6-cyano-5-[bis(ethoxycarbonylmethyl)carbamoyloxy]-1 H-pyrrolo[1 ,2-b][1 ,2,4]triazole-7-carboxylic acid-2,6-di-tert-butyl-4-methyl-cyclohexyl ester (UC-141) were investigated. The toxicokinetic properties of the substance were assessed taking into account the available information on physico-chemical and toxicological characteristics, according to ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2012).

 

The substance is a free flowing, white powder at room temperature (20 °C). The molecular weight (MW) is 747.92 and the log Pow 7.7 at room temperature (van Boxtel, 2011), indicating that the substance is not bioavailable via the oral route, according the ‘Lipinski rule of 5’ (Lipinski et al., 2001). The substance is practically insoluble in water (<0.08 mg/L at 20 °C; Brekelmans, 2003), which is generally a limiting factor of gastrointestinal absorption. However, the combination with a log Pow > 4 may favour a direct uptake via the lymphatic system.

 

Absorption

Oral

In an acute oral toxicity study performed according to OECD Guideline 423, rats were administered 2000 mg/kg bw UC-141 by gavage (Hooiveld, 2003a). There was no mortality, leading to an LD50 cut-off value of 5000 mg/kg bw (as defined in the guideline). Uncoordinated movements or a hunched posture was noted in all 5 males 2-4 hours after administration, lasting up to 2 days (probably due to discomfort caused by the gavage treatment). No clinical signs were observed in the females.

In a range-finding study, in which males (3/group) were administered 150 and 1000 mg/kg bw/day by gavage for 5 consecutive days no treatment-related effects were observed (Hooiveld, 2004b). In the main study, performed according to OECD Guideline 407, rats were dosed 50, 150 and 1000 mg/kg bw/day by gavage for 28 days (Hooiveld, 2004b). No toxicologically relevant effects were noted at any dose level, leading to a NOAEL ≥ 1000 mg/kg bw/day. There were no changes in liver weight or enzyme activity in the treatment group compared to the control group, which generally indicates an increased metabolic load caused by the administered substance. Generally, a lack of systemic effects both during the acute and subacute studies indicates the substance has limited oral bioavailability. This is supported by the physico-chemical properties of the substance. The very low water solubility (<0.08 mg/L) and the high lipophilicity (log Pow = 7.7) also predicts, that UC-141 have limited oral absorption. In general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract. In the presence of food and bile salts the solubility might be somewhat increased (Groen, 2004). UC-141 may be taken up by micellar solubilization due to its high partition coefficient (log Pow = 7.7) and enter the systemic circulation via the lymphatic system. However, in general the the oral absorption of UC-141 is considered to be low.

Dermal

The effect of dermal administration of the substance was assessed in an acute dermal toxicity study in rats according to OECD Guideline 402 (Hooiveld, 2004b). A limit dose of 2000 mg/kg bw caused flat or hunched posture in 4/5 males and 5/5 females up to 6 days after administration. Chromodacryorrhoea was noted in 2/5 males and 3/5 females from 2 hours after administration and lasted until Day 2 for 1/5 males and 2/5 females. These reactions are frequently stress-related, but considering the duration they are possibly treatment-related or substance-related. No systemic effects were observed after the topical application of up to 0.5 g in the irritation and sensitisation studies (Hooiveld, 2003b; 2003d).

Due to its high lipophilicity (log Pow = 7.7) uptake into the stratum corneum and transfer between stratum corneum and epidermis is likely to be very slow. Additionally, the low water solubility (< 0.08 mg/L) suggests that dermal uptake in general is low. The QSAR tool EpiSuite was applied to calculate the dermal absorption, using the molecular weight, log Po/w and water solubility values (US EPA, 2011). A dermal absorption rate of 0.0904 µg/cm²/h was predicted. Taking all data together, the dermal absorption for UC-141 is considered to be negligible.

 

Inhalation

A substance may also be absorbed via the respiratory system. As the vapour pressure is 0.0045 Pa (at 20 °C), the inhalation potential due to evaporation is very low. The substance is a powder with an inhalable fraction (MMD 84.8 µm). Less than 75% of the particles were ≤ 100 µm, while < 10% was ≤ 25.5 µm. Generally only particles < 4 µm reach the lungs (bronchioles), indicating that a negligible amount of the substance will enter the lower respiratory system. The majority of the inhaled particles will be trapped on the mucous membrane in the trachea and bronchi, from where they will be transported by ciliary movement upwards to the throat and be swallowed or coughed out. Based on these data, the absorption of the substance via the inhalative route is considered to be low.

 

Distribution

If a molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

The log Pow value of 7.7 and polarity of the molecule indicate that the substance can reach all tissues, including fatty tissues.

 

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. An important role plays the liver where many metabolites may arise.

The potential metabolites following enzymatic metabolism of the substance were predicted using the QSAR OECD toolbox (OECD, 2012). This QSAR tool predicts which metabolites of the test substance may be created by enzymes in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Twenty-nine (29) hepatic metabolites were predicted. Primarily, one of the ester bonds are hydrolysed. Based on the size of the metabolites, they may be hydrolysed further or conjugated in phase II-reactions and then be excreted. The parent molecule may also be hydrolysed on several sites, making it more water-soluble and susceptible to metabolism by phase II-enzymes. In the skin, 6 metabolites were predicted, similar to those expected in the liver. A C-N-bond is broken or hydrolysis of a C-molecule is predicted. The metabolites are expected to enter the blood circulation and have the same fate as the hepatic metabolites. 

There is no indication that the substance is activated to reactive intermediates under the relevant test conditions. The studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) were negative, with and without metabolic activation (Buskens, 2003; Bednáriková, 2013; Buskens, 2004).

 

Excretion

The fraction of the test substance that is not absorbed via the gastrointestinal tract will be excreted via the faeces, mainly unmetabolised due to the low water solubility. In the fraction that is absorbed, the metabolites will have a range of molecular weights, depending on the extent of metabolism. The metabolites with a molecular weight above 300 will most likely be excreted rapidly via the bile, while those with a molecular weight lower than 300 are likely to be excreted rapidly via the urine. Therefore, accumulation in the body during prolonged exposure will be very low, although some retention in fatty acids may occur (Groen, 2004).

 

 

Reference list

ECHA. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Nov 2012. Downloaded from: http://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf

 

Groen K. (2004) Toxicokinetic Assessment of UC-141. Testing laboratory: NOTOX B.V., DD s-Hertogenbosch, The Netherlands, Report no. 400253. Owner company: Fujifilm Manufacturing Europe B.V., Tilburg, The Netherlands. Report data: 2004-07-16

 

Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev.;46(1-3):3-26.

 

OECD, 2012. (Q)SAR Toolbox v2.3. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 16 August 2012.http://toolbox.oasis-lmc.org/?section=overview

 

US EPA, 2011. Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.10. United States Environmental Protection Agency, Washington, DC, USA. Calculation performed 16 August 2012.