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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert report

Adequacy of study:

key study

Study period:

16 July 2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This expert report was compiled using study data and information from publications. The study data used was performed under GLP conditions and in accordance with standardised guidelines at the same testing facility where the author of this report was based. The information provided is in accordance with generally accepted scientific principles and the information is considered reliable with restrictions.

Data source

Reference

Reference Type:

other: Expert Assessment

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The information provided on the absorption, distribution, metabolism and excretion of the test substance has been taken from a toxicokinetic assessment. The assessment was performed using relevant and reliable study data by an expert at the testing facility where the experimental work was carried out. An extensive toxicokinetic assessment was considered unnecessary and considered to be of limited value given the low mammalian toxicity observed in acute oral and dermal toxicity tests (LD50 > 2000 mg/kg bw for both) and a subacute oral toxicity test (NOAEL 1000 mg/kg/day). This summary provides the anticipated toxicokinetic behaviour of the test substance.

GLP compliance:

no

Remarks:

Not applicable to an expert report

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

448-050-6

EC Name:

-

Cas Number:

444065-11-6

Molecular formula:

C41 H57 N5 O8

IUPAC Name:

2,6-di-tert-butyl-4-methylcyclohexyl 5-{[bis(2-ethoxy-2-oxoethyl)carbamoyl]oxy}-2-(4-tert-butylphenyl)-6-cyano-1H-pyrrolo[1,2-b][1,2,4]triazole-7-carboxylate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): UC-141
- Substance type: White powder

Radiolabelling:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The water solubility of the test substance is extremely low, caused by the large size of the molecule and the presence of the strongly apolar groups. Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that the substance will show a high systemic exposure after oral administration as a dry substance. However, in the presence of food and bile salts, the solubility might be somewhat increased and thus the systemic exposure might be somewhat higher. For compounds with a high partition coefficient like this substance, direct uptake via the lymph is sometimes observed. It is to be expected that the oral bioavailability, and thus the systemic exposure, of the substance will be very low (reference 1).
Uptake via inhalation will be negligible because of the particle size (10 % < 25.46 µm).
Since it is generally accepted that substances with log Pow ranging from 0.1 to 6 penetrate the skin easily (reference 2), it is not to be expected that the substance (with a calculated log Pow value of 11.4) will penetrate the skin.

Details on distribution in tissues:

The test substance will show a high volume of distribution, because of the high lipophilicity of the compound. It will be extensively distributed into peripheral tissue, especially fatty tissues. The plasma protein binding is expected to be high.

Details on excretion:

Excretion is expected to be rapid via bile and/or urine.

Metabolite characterisation studies

Details on metabolites:

Theoretically, in the gastro-intestinal tract, the amide group may undergo cleavage, resulting in more polar break-down products. However, because of the low solubility of the test substance this is not anticipated.
If absorption of the test substance occurs, the unsaturated rings will undergo extensive hydroxylation, followed by rapid sulfation or glucuronidation (reference 3). The resulting metabolites will be excreted via bile and/or urine.
Additionally, cleavage of the ester bonds is anticipated. The resulting metabolites will be excreted via bile and/or urine.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: low bioaccumulation potential based on expert assessment
Based on the expected kinetic behaviour in the body, the test substance will hardly be absorbed after oral administration, mainly because of its low solubility. If absorption occurs, the substance will be extensively metabolised in the liver and rapidly excreted via bile and/or urine. Therefore, accumulation in the body during prolonged exposure will be very low, although some retention in fatty tissues may occur.

Executive summary:

The information provided on the absorption, distribution, metabolism and excretion of the test substance has been taken from a toxicokinetic assessment. The assessment was performed using relevant and reliable study data by an expert at the testing facility where the experimental work was carried out.

An extensive toxicokinetic assessment was considered unnecessary and considered to be of limited value given the low mammalian toxicity observed in acute oral and dermal toxicity tests (LD50 > 2000 mg/kg bw for both) and a subacute oral toxicity test (NOAEL 1000 mg/kg/day). This summary provides the anticipated toxicokinetic behaviour of the test substance. 

 

Absorption

The water solubility of the test substance is extremely low, caused by the large size of the molecule and the presence of the strongly apolar groups. Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that the substance will show a high systemic exposure after oral administration as a dry substance. However, in the presence of food and bile salts, the solubility might be somewhat increased and thus the systemic exposure might be somewhat higher. For compounds with a high partition coefficient like this substance, direct uptake via the lymph is sometimes observed. It is to be expected that the oral bioavailability, and thus the systemic exposure, of the substance will be very low.

Uptake via inhalation will be negligible because of the particle size (10 % < 25.46 µm).

Since it is generally accepted that substances with log Pow ranging from 0.1 to 6 penetrate the skin easily, it is not to be expected that the substance (with a calculated log Pow value of 11.4) will penetrate the skin.

 

Distribution

The test substance will show a high volume of distribution, because of the high lipophilicity of the compound. It will be extensively distributed into peripheral tissue, especially fatty tissues. The plasma protein binding is expected to be high.

 

Metabolism and Excretion

Theoretically, in the gastro-intestinal tract, the amide group may undergo cleavage, resulting in more polar break-down products. However, because of the low solubility of the test substance this is not anticipated.

If absorption of the test substance occurs, the unsaturated rings will undergo extensive hydroxylation, followed by rapid sulfation or glucuronidation. The resulting metabolites will be excreted via bile and/or urine.

Additionally, cleavage of the ester bonds is anticipated. The resulting metabolites will be excreted via bile and/or urine.

 

Based on the expected kinetic behaviour in the body, the test substance will hardly be absorbed after oral administration, mainly because of its low solubility. If absorption occurs, the substance will be extensively metabolised in the liver and rapidly excreted via bile and/or urine. Therefore, accumulation in the body during prolonged exposure will be very low, although some retention in fatty tissues may occur.