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 significant absorption of the substance is expected via any route.  For risk assessment purposes the oral and inhalation absorption values are considered to be <1% and the dermal absorption value is considered to be 0%.  A biodegradation study did not indicate any rapid biodegradation and extensive metabolism is not expected.  The high Pow would imply preferential partition to fatty tissues.  The high MW would predicate excretion of any absorbed material via the bile.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Introduction

The physico-chemical properties and the results ofin vitrostudies and acute and repeat dose toxicity studies with animals for ‘529A coupler’ (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), also known as UC-141, have been used to determine a toxicokinetic profile. The structure of 529A coupler is show in Figure 1 (attached).

Physicochemical properties

The substance is a white powder and has the molecular formula C₄₁H₅₇N₅O₈ with a molecular weight of 747.9 g/mol. It is of very low water solubility (0.08 mg/L at 20°C) with a log Pow value of 11.4 at 25°C. It is hydrolytically stable, and not readily biodegradable (In an OECD 301B ready biodegradation study, the test substance, at a concentration of ca. 18 mg/L (12 mg TOC/L), was incubated in activated sludge for 28 days at 20 ± 2°C. At the end of the test, a maximum of 13% of the material had been biodegraded). 

Absorption

Oral 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 there will high systemic exposure after oral administration as the dry substance. However, in the presence of food and bile salts, the solubility might be increased. 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.  No toxicologically significant oral absorption of the substance is expected. This is supported by data fromin vivotoxicology studies including an OECD 421 reproductive screening study (Török-Bathó, 2014, tested up to the limit dose of 1000 mg/kg/day), and OECD 407 repeat dose oral toxicity study (Hooiveld, 2004, tested up to the limit dose of 1000 mg/kg/day), and an OECD 423 (Hooiveld, 2003, tested up to a dose of 5000 mg/kg), where no effects observed that would give any indication that any absorption had taken place across the gastro-intestinal tract.

 

Oral absorption is anticipated to be <1%.

Dermal absorption

The extreme log Pow value (>11), the large molecular weight and that this material is an insoluble solid, will prevent any measurable dermal absorption. In an OECD 402 acute dermal toxicity (Hooiveld, 2004, tested up to 2000 mg/kg bw) there were no effects observed that would give any indication that any dermal absorption had taken place.

 

Dermal absorption is anticipated to be 0%.

 

Inhalation absorption

Uptake via inhalation will be negligible because of the particle size (10% <25.46 µm). Inhalation exposures will be converted to oral exposures.

 

Inhaled material is anticipated to be removed to the gut by the mucocilliary escalator, whereupon absorption is anticipated to <1%.

Distribution

Because of the high lipophilicity of the compound, if any significant absorption took place (not anticipated) it would partition highly preferentially to fatty tissues.

Metabolism

In an OECD 301B ready biodegradation study (Desmares-Koopmans, 2003) the test substance, at a concentration of ca. 18 mg/L (12 mg TOC/L), was incubated in activated sludge for 28 days at 20 ± 2°C. At the end of the test, the material reached at most 13% biodegradation. Therefore it is anticipated that no significant mammalian metabolism would occur prior to excretion either in the gut or if absorbed. 

Elimination

Given the high molecular weight (>300) any absorbed material is anticipated to be excreted via the bile.

Conclusion

No significant absorption of the substance is expected via any route. For risk assessment purposes the oral and inhalation absorption values are considered to be <1% and the dermal absorption value is considered to be 0%. A biodegradation study did not indicate any rapid biodegradation and extensive metabolism is not expected. The high Pow would imply preferential partition to fatty tissues. The high MW would predicate excretion of any absorbed material via the bile.