Methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

Endpoint summary

Description of key information

Following single oral (gavage) administration of the isotopic Rhodiasolv Polarclean mixture at dose-levels of 1000 and 2000 mg/kg, and 2.2 MBq/kq of [14C]-Rhodiasolv Polarclean to male Sprague-Dawley rats, the test item was well tolerated. The maximum plasma concentration was reached 0.25 hours post-dosing for both dose-levels and the terminal half-life values were similar. The plasma exposure increased dose proportionally between 1000 and 2000 mg/kg.
The test item was almost entirely absorbed, with percentage of absorption of 100.1%. The overall elimination of the radioactivity occurred within 24 hours after administration and mainly in urine. Only 1.2% of the dose was found in feces. Recovery was complete at 101.2%.
The radioactivity was mainly observed in the gastrointestinal tract 0.25 hours after oral administration and distributed in the other tissues (liver, spleen, kidney and fat) at low concentration levels. Nevertheless, at 168 hours post dosing, the radioactivity levels in all tissues were below the Limit Of Quantification, confirming the complete elimination of the test item.
Two metabolites without the presence of the parent drug were found in urine and only one metabolite in plasma. The main metabolite in urine was also seen in plasma. This suggests a complete metabolization of the test item.
Based on available toxicological data, physico-chemical properties and a QSAR analysis, absorption of Rhodiasolv Polarclean through the skin is expected to be limited.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100.1

Additional information

One ADME study was performed in rat to investigate the blood and plasma pharmacokinetics, mass balance and tissue distribution of total radioactivity following oral exposure of Rhodiasolv Polarclean (Key study, Sabadie, 2014). In addition, a QSAR analysis was conducted to estimate the dermal absorption of the registered substance.

ORAL ROUTE:

An ADME study was performed according to OECD 417 guideline and in compliance with GLP to investigate the blood and plasma pharmacokinetics, mass balance and tissue distribution of total radioactivity following a single oral (gavage) administration of radiolabelled test item, [¹⁴C]-Rhodiasolv Polarclean,in male Sprague-Dawley rats. In addition the presence of metabolites in plasma and urine was investigated.

Method:

Thirty two Sprague-Dawley male rats were allocated to four groups and were orally (gavage) treated on a single occasion (Day 1), as follows:

- Groups 1 and 2, twelve rats/group treated at the dose-levels of 2.2 MBq/kg and 1000 mg/kg and 2000 mgkg, respectively for Pharmacokinetic evaluation,

-  Group 3, four rats treated at the dose-levels of 2.2 MBq/kg and 2000 mg/kg for evaluation of the mass balance and tissue distribution,

. Group 4, four rats treated at the dose-levels of 2.2 MBq/kg and 2000 mg/kg for evaluation of the tissue distribution. 

 

Results:

Pharmacokinetic analysis:

Mean total radioactivity levels were quantifiable in plasma from the first time-point of 0.25 to 8 hours for both dose-levels (1000 and 2000 mg/kg). The maximum mean plasma total radioactivity was reached at 0.25 hours after oral administration. Then the mean total radioactivity had tendency to decrease until 8 hours in a multi-compartmental manner.

The terminal half-life values were similar for both dose levels with 5.3 and 4.0 hours at 1000 and 2000 mg/kg, respectively. The plasma exposure based on Cmax and AUC0-t had tendency to increase dose‑proportionally between 1000 and 2000 mg/kg, as the dose normalized ratios were ranged from 0.406 to 0.530 for Cmax and from 0.743 to 0.843 for AUC0-t.

 

Mass Balance:

Following single oral (gavage) administration, the mean total cumulative excretion in urine, feces and cage wash of the administered radioactive dose, over a 168-hour period, was 101.2%.

The radioactivity was eliminated mainly in the urine. Specifically, 88.3% of the dose over the study period was measured in the urineversus1.2% in the feces.

The administered radioactivity was excreted rapidly (within the first 24 hours after administration). For the feces, most of radioactive dose was also eliminated rapidly (within the first 24 hours after administration).

Following single oral (gavage) administration at a dose-level of 2000 mg/kg and 2.2 MBq/kg to male Sprague-Dawley rats, the mean cumulative percentage of absorption, over a 168-hour period, was 100.1% of the dose administered.

 

Tissue distribution:

Following single oral (gavage) administration, the radioactivity levels were quantifiable at 0.25 hours (corresponding to the T_max) in all tissues. Specifically, the radioactivity was mainly in the gastrointestinal tracts, with 91.8% of dose administered. In other tissues (liver, spleen, fat and kidney), the radioactivity levels were below than 2% of the administered dose. In contrast, 168 hours after treatment, the radioactivity levels were below the limit of quantification in all tissues.Metabolic pattern:

Metabolic pattern analysis in plasma samples at the time-points 0.25 and 0.5 hours showed the presence of one metabolite without presence of the parent drug. Moreover, metabolic pattern analysis in urine fraction 0-6 and 6-24 hours showed the presence of two metabolites without presence of the parent drug. The main metabolite in urine was also seen in plasma.

 

In conclusion, following single oral (gavage) administration of the isotopic Rhodiasolv Polarclean mixture at dose-levels of 1000 and 2000 mg/kg, and 2.2 MBq/kq of [¹⁴C]-Rhodiasolv Polarclean to male Sprague-Dawley rats, the test item was well tolerated. The maximum plasma concentration was reached 0.25 hours post-dosing for both dose-levels and the terminal half-life values were similar. The plasma exposure increased dose‑proportionally between 1000 and 2000 mg/kg.

The test item was almost entirely absorbed, with percentage of absorption of 100.1%. The overall elimination of the radioactivity occurred within 24 hours after administration and mainly in urine. Only 1.2% of the dose was found in feces. Recovery was complete at 101.2%.

The radioactivity was mainly observed in the gastrointestinal tract 0.25 hours after oral administration and distributed in the other tissues (liver, spleen, kidney and fat) at low concentration levels.

DERMAL ROUTE:

There was no evidence of systemic toxicity in the acute dermal toxicity study in rats at the dose of 2000 mg/kg bw.

There were also no signs of toxicity and no sensitisation effects after cutaneous exposure on the mouse ears in the LLNA assay.

 In addition, although the molecular weight is relatively small (187.12), the log Po/w of 0.39, water solubility (>490 g/L at 24°C) and estimated permeability coefficient (0.000253 cm/hr based on DERMWIN model) tend to support a limited capacity for absorption through the skin.

 

Reference:

US Environmental Protection Agency (2011). DermWin v 2.01. EPI Suite.