3,3'-dimethylbiphenyl-4,4'-diyl diisocyanate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert Judgement

Type of information:

other: Expert Judgement

Adequacy of study:

key study

Study period:

2010

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

other: Expert statement

Principles of method if other than guideline:

Rational argumentation based in physico-chemical properties of TODI and read-across from similar substance

Radiolabelling:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Remarks:

Doses / Concentrations:
not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Preliminary studies:

not applicable

Details on absorption:

Data on the absorption or the metabolic fate and thus information on the toxicokinetics in humans of absorbed TODI is very limited.
No information is available on the toxicokinetics of TODI or e.g. "MDI" (methylene diphenyl diisocyanate, similar compound to TODI) following oral exposure in animals. But due to its high reactivity, orally ingested TODI will undergo spontaneous hydrolysis upon reaching the stomach as degradation products that are insoluble in water and thus TODI is not likely to cross gastrointestinal-tract membranes. Taken together, absorption in the gastrointestina-tract of TODI and consequently bioavailability is rather unlikely.

Details on distribution in tissues:

no data available

Details on excretion:

Excretion is likely to occur in form of GSH-conjugates. It is assumed to appear mainly via faeces (similar as shown in a study with MDI: 5% via urine and 79% in faeces).

Details on metabolites:

no data available

Bioaccessibility (or Bioavailability) testing results:

no data available

No tendency for bioavailability and bioaccumulation is expected

Description of key information

The substance has a very low to negligible bioavailability and bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Very low to negligible bioavailability and bioaccumulation

The unique feature common to all diisocyanates is that they consist of two N=C=O (isocyanate) functional groups attached to an aromatic or aliphatic parent compound. Because of the highly unsaturated nature of the isocyanate functional group, the diisocyanates readily react with compounds containing active hydrogen atoms (electrophiles). Thus, the diisocyanates readily react with water (humidity), alcohols, amines, etc. Due to its main chemical property designed for the compound’s use, TODI has a very limited stability in water, as it rapidly reacts upon contact with water. Thus, all toxicokinetic analyses have to consider that TODI is designed to rapidly react upon contact with water, resulting in degradation products that are insoluble in water and organic solvents. In general isocyantes react rapidly with water at ordinary temperatures, giving rise to 1.3-disubstituted ureas and carbon dioxide. Due to the very low water solubility (calculated: 0.1128 mg/L at 25 degree C) and fast hydrolysis an experimental determination of the partition coefficient of TODI or Bioconcentration factors (BCF) are technically not feasible. The calculated values for a potential degradation product (TODA: 4,4'-bi-o-toluidine; 3,3'-Dimethyl-4,4'-diamino-biphenyl, CAS no. 119 -93 -7, EC no. 204 -358 -0) are 2.34 to 3.02 in case of log Pow and 16.25 in case of BCF. Thus, no tendency to bioaccumulation is expected.

Adsorption and excretion

Data on the absorption or the metabolic fate and thus information on the toxicokinetics in humans of absorbed TODI is very limited. No information is available on the toxicokinetics of TODI or e.g. "MDI" (methylene diphenyl diisocyanate, similar compound to TODI) following oral exposure in animals. But due to its high reactivity, orally ingested TODI will undergo spontaneous hydrolysis upon reaching the stomach as degradation products that are insoluble in water and thus TODI is not likely to cross gastrointestinal-tract membranes. Taken together, absorption in the gastrointestina-tract of TODI and consequently bioavailability is rather unlikely. Even if orally or dermally absorbed, TODI's toxicity is very low due to the low water solubility and bioavailability. Acute oral and dermal toxicity studies with TODI revealed a LD50 > 2000 mg/kg in a limit dose test. As the lower proportion, TODI is likely excreted in form of GSH-conjugates via urine. Excretion is supposed to appear mainly via faeces (similar as shown in a study with MDI: 5% via urine and 79% in faeces).

Sensitisation potential

Due to the high reactivity with hydroxyl-, amin-, carboxyl and mercaptogroups the permeation and absorption of intact isocyanates through the skin or the mucosa of the respiratory tract is quite improbable but this reactivity may explain the sensitisation potential of TODI: The high reactivity of TODI with nucleophilic biomolecules promotes immunological reactions and consequently TODI showed a sensitisation potential (sensitiser) in a maximisation study. The mechanism behind isocyanate-related hypersensitivity is still obscure. Immediate allergic, late allergic and dual-phase responses can occur. Humoral as well as cellular immunity may be involved in the pathogenesis of hypersensitivity due to isocyanates. The specific humoral response can be IgE as well as IgG mediated. Cross-reactivity with other isocyanates has been described in several publications. Consequently, although there is no respective result from a inhalation study available for TODI, and based on the fact that similar substances as e.g. MDI (CAS no. 9016-87-9) and 4,4'-Methylendicyclohexyldiisocyanat (CAS no. 5124-30-1; EC no. 225-863-2) are classified for skin and respiratory sensitisation cat. 1 it is to be assumed that TODI "may cause allergy or asthma symptoms or breathing difficulties if inhaled" (H334).