Carbamic acid, N-[[5-[[[2-[2-(dimethylamino)ethoxy]ethoxy]carbonyl]amino]-1,3,3-trimethylcyclohexyl]methyl]-, 2-[2-(dimethylamino)ethoxy]ethyl ester

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert judgement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Part of the SNIF file, which was accepted by the Belgian national authority for NONS.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2002

Materials and methods

Objective of study:

other: Assessment of toxicokinetic behaviour

Principles of method if other than guideline:

Not reported in SNIF file.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

441-100-8

EC Name:

-

Cas Number:

351197-46-1

Molecular formula:

Hill formula: C24 H48 N4 O6 CAS formula: C24 H48 O6 N4

IUPAC Name:

2-[2-(dimethylamino)ethoxy]ethyl N-{[1,3,3-trimethyl-5-(9-methyl-2-oxo-3,6-dioxa-1,9-diazadecan-1-yl)cyclohexyl]methyl}carbamate

Test animals

Species:

other: no data

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

other: oral and dermal

Vehicle:

not specified

Duration and frequency of treatment / exposure:

from acute exposure up to 28 days

Doses / concentrations

Remarks:

Doses / Concentrations:
up to 2000 mg/kg bw acute

No. of animals per sex per dose / concentration:

acute: 3

Control animals:

not specified

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The early onset of toxic effects may indicate a rapid absorption of the substance in the stomach. Although to some extent polar as corroborated by the high water solubility, the substance may be readily taken up by the gastric mucosa: The molecular weight (< 1000) and the log Pow of the substance (> 1) may indicate a facilitated passive diffusion through the lipophilic phase of the gastric mucous membrane. It also has to be considered that ionisation of the substance at low pH (e.g. protonization of amine groups) may take place and influence the location of resorption in the gastrointestinal duct. Further, based on the above- mentioned hydrolysis results it might be assumed that the substance is not significantly hydrolysed at low pH before absorption in the stomach.

Since it is generally accepted that substances with log Pow ranging from 0.1 to 6 penetrate the skin easily, it is to be expected that the substance will be absorbed to some extent through the skin. This assumption is corroborated by the skin sensitising effect observed.

Details on distribution in tissues:

The sub-acute 28-day oral toxicity yielded a NOAEL value of 150 mg/kg/day. Mortality was observed in 6 animals at 450 mg/kg/day. Since clinical signs were observed only at 450 mg/kg/day it can be assumed that possible toxic metabolites will not accumulate in the body after prolonged exposure. Moreover, since the substance is highly water soluble, though slightly lipophilic (log Pow 1.4), an accumulation in fatty tissues is not probable. The substance is anticipated to be distributed from the portal vein blood into the liver, and further into the blood plasma, bone marrow and other organs.

Details on excretion:

not addressed

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

E.g. oxidative dealkylation of the amino- and ether-groups may occur. The formed metabolites of the substance might lead to toxic effects as indicated by a dose-related increase in LDH and AST activity in hepatocytes and dose-related decrease of reticulocytes in the blood.