reaction product of diphenylmethanediisocyanate, octylamine, 4-ethoxyaniline and ethylenediamine (1:0,37:1,53:0,05)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

expert statement

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: expert statement

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

no guideline required

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

430-750-8

EC Name:

-

Cas Number:

1266545-86-1

Molecular formula:

Not applicable (UVCB substance)

IUPAC Name:

Reaction product of (C8 – C18) aliphatic primary amines, ethylene diamine, p-phenetidine with 4,4’-methylenediphenyl diisocyanate

Test animals

Details on test animals or test system and environmental conditions:

Not applicable

Administration / exposure

Details on exposure:

Not applicable

Duration and frequency of treatment / exposure:

Not applicable

No. of animals per sex per dose / concentration:

Not applicable

Details on study design:

Not applicable

Details on dosing and sampling:

Not applicable

Statistics:

Not applicable

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The water solubility of Urea 4 is very poor (<= 1 mg/L at 20°C). Therefore, the dissolution is regarded to be the rate limiting step in the absorption process from the gastro-intestinal tract. Based on its molecular structure and from investigations on degradation in water, hydrolysis is not expected to take place in the stomach and the substance should pass the stomach without any changes. As Urea 4 has lipophilic properties (log Pow: > 6) and is poorly water soluble, the substance has to be solubilised in the organism (e.g. by means of acidic bile salts) before the compound can be absorbed and becomes bioavailable. As a consequence, most of Urea 4 will not be absorbed but efficiently excreted with the faeces.

Details on distribution in tissues:

Small amounts absorbed, if any, are distributed within the organism by systemic circulation. Due to the log Pow of > 6, absorbed quantities of Urea 4 can bind to plasma proteins and bioaccumulation in fat tissue cannot be excluded.

Details on excretion:

Most of Urea 4 will not be absorbed but efficiently excreted with the faeces. After absorption of small amounts, Urea 4 may be metabolised in the liver by phase I and phase II enzymes. The resulting functionalised metabolites are highly water soluble and may be efficiently excreted with the urine and the faeces. With regards to the high molecular weight and the lipophilicity of the parent compound as well as the molecular weights of the potential metabolites, it has to be considered, that a high amount of these compounds can be reabsorbed within the kidney tubule and, for this case, biliary excretion may be the predominant pathway of elimination.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Following absorption of small quantities of Urea 4, the substance can be metabolised by the hepatic system:
Phase I enzymes can induce N-dealkylation and the hydroxylation of aromatic ring-systems. N-dealkylation will result in the respective aldehydes and amino compounds that can be further oxidised by phase I enzymes and conjugated. In case of the tetra-urea the respective diureas can be formed. Also, it has to be taken into account that Urea 4 can be hydrolysed by amidases to yield the respective smaller and more polar fragments like amines and carboxylic acids, which could be further conjugated in phase II reaction processes. Functionalised metabolites and the phenolic group of the substituent phenetidine can be conjugated with glucuronides, sulfates and amino acids to result in highly water soluble metabolites.

Applicant's summary and conclusion

Conclusions:

Based on the expected kinetic behaviour in the body, substantial amounts of Urea 4 will neither be absorbed nor accumulated in the body. Due to the in situ synthesis of Urea 4 in a matrix (mineral oil) and its exclusive use therein, a direct contact to humans with this substance can be excluded. The described kinetic behaviour is supported by the molecular structure of Urea 4, its physico-chemical properties and the acute and short-term (28-day oral) toxicity studies.

Executive summary:

General information on Urea 4:

Molecular weight range: 508.76 - 834.98 g/mol

Aggregate state: solid (powder) at RT

Vapour pressure: 2 x 10 E-16 Pa at 25°C

Water solubility: <= 1 mg/L at 20 °C (estimated)

Log Pow: > 6 (estimated)

Urea 4 has a very low oral and dermal toxicity with a LD50 value of > 2,000 mg/kg bw. The substance is neither an irritant to skin nor to eyes and not sensitising. After repeated oral administration (28 -day toxicity study) of Urea 4 to rats, no adverse substance-related effects were observed up to a dose level of 1000 mg/kg bw/day. In in vitro test systems Urea 4 did not exhibit a mutagenic potential. Therefore, an extensive toxicokinetic assessment of the substance is considered of limited value. In the present study, the expected toxicokinetic behaviour of Urea 4 is described qualitatively, using the information available from the base-set data.

Toxicokinetic:

The water solubility of Urea 4 is very poor (<= 1mg/L). Therefore, the dissolution is regarded to be the rate limiting step in the absorption process from the gastro-intestinal tract. Based on its molecular structure and from investigations on degradation in water, hydrolysis is not expected to take place in the stomach and the substance should pass the stomach without any changes.

As Urea 4 has lipophilic properties (log Pow: > 6) and is poorly water soluble. The substance has to be solubilised in the organism (e.g. by means of acidic bile salts) before the compound can be absorbed and becomes bioavailable. As a consequence, most of Urea 4 will not be absorbed but efficiently excreted with the faeces. Small amounts absorbed, if any, are distributed within the organism by systemic circulation. Due to the log Pow of > 6, quantities that are absorbed may bind to plasma proteins and a certain bioaccumulation in fat tissue cannot be excluded.

Following absorption of small quantities of Urea 4, the substance can be metabolised by the hepatic system. Phase I enzymes can induce N-dealkylation and the hydroxylation of aromatic ring-systems. N-dealkylation will result in the respective aldehydes and amino compounds that can be further oxidised by phase I enzymes and conjugated. In case of the tetra-urea the respective diureas can be formed. Also, it has to be taken into account that Urea 4 can be hydrolysed by amidases to yield the respective smaller and more polar fragments like amines and carboxylic acids, which could be conjugated in phase II reaction processes.

Functionalised metabolites can be conjugated with glucuronides, sulfates and amino acids to result in highly water soluble metabolites that will be efficiently excreted with the urine and the faeces. With respect to the molecular weight and the lipophilicity of the parent compound, as well as the molecular weights of the potential metabolites, it has to be considered, that a high amount of these compounds can be reabsorbed within the kidney tubule and, in this case, biliary excretion may be the predominant pathway of elimination. Based on the expected kinetic behaviour in the body, substantial amounts of Urea 4 will neither be absorbed nor accumulated in the body. Due to the in situ synthesis of Urea 4 in a matrix (mineral oil) and its exclusive use therein, a direct contact to humans with this substance can be excluded. The described kinetic behaviour is supported by the molecular structure of Urea 4, its physico-chemical properties and the acute and short-term (28 -day oral) toxicity studies. In the latter no substance-related adverse effects could be observed up to 1000 mg/kg bw/day (= NOAEL).