reaction product of diphenylmethanediisocyanate, toluenediisocyanate ( reaction mass of isomers: 65 % 2,4- and 35 % 2,6-diisocyanate), octylamine, oleylamine and 4-ethoxyaniline (molar ratio 3.88:1:6.38:0.47:2.91)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

1999

Reliability:

1 (reliable without restriction)

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:

430-970-4

EC Name:

-

Cas Number:

1266545-66-7

Molecular formula:

Not applicable (UVCB substance)

IUPAC Name:

Reaction product of (C8 – C18) aliphatic primary amines (partly unsaturated) and p-phenetidine with a mixture of aromatic isocyanates comprising of primarily 4,4’-methylenediphenyl diisocyanate and 4-methyl-m-phenylene

Details on test material:

NA

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

Doses / concentrations

Remarks:

Doses / Concentrations:
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 the test substance 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 the test substance has lipophilic properties (log Pow: > 5) 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 the test substance will be not 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 > 5, absorbed quantities of the test substance can bind to plasma proteins and bioaccumulation in fat tissue cannot be excluded.

Details on excretion:

Most of the test substance will not be absorbed but efficiently excreted with the faeces. After absorption of small amounts, the test substance 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 the test substance, the substance can be metabolised by the hepatic system:
Phase I enzymes can induce N-dealkylation and the hydroxylation of the exocyclic methyl group and 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. Also, it has to be taken into account that the test substance 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 can be conjugated with glucuronides, sulfates and amino acids to result in highly water soluble metabolites.

Applicant's summary and conclusion

Conclusions:

No bioaccumulation potential based on a toxicokinetic assessment
Based on the expected kinetic behaviour in the body, substantial amounts of the test substance will neither be absorbed nor accumulated in the body. Due to the in situ synthesis of the test substance 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 the test substance, its physico-chemical properties and the acute and short-term (28-day oral) toxicity studies.

Executive summary:

General information on the test substance:

Molecular weight range: 432.64 - 785.26 g/mol

Aggregate state: solid (powder) at RT

Vapour pressure: < 8 x 10 E-12 Pa at 25°C

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

Log Pow: > 5 (estimated)

The test substance 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 the test substance to rats, no adverse substance-related effects were observed up to a dose level of 1000 mg/kg body weight per day. In in vitro test systems the test substance 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 the test substance is described qualitatively, using the information available from the base-set data.

Toxicokinetic:

The water solubility of the test substance 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 the test substance has lipophilic properties (log Pow: > 5) 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 the test substance 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 > 5, 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 the test substance, the substance can be metabolised by the hepatic system. Phase I enzymes can induce N-dealkylation and the hydroxylation of the exocyclic methyl group and 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. Also, it has to be taken into account that the test substance 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 the test substance will neither be absorbed nor accumulated in the body. Due to the in situ synthesis of the test substance 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 the test substance, 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).