2,5-bis-isocyanatomethyl-bicyclo[2.2.1]heptane

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: toxicokinetic assessment

Adequacy of study:

key study

Study period:

April - December 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Toxicokinetic assessment by a certified toxicologist

Qualifier:

according to guideline

Guideline:

other: ECB EU Technical Guidance Document on Risk Assessment, 2003

Qualifier:

according to guideline

Guideline:

other: Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance

GLP compliance:

no

Type:

absorption

Results:

For risk assessment purposes: oral absorption 100%, inhalation absorption 100% and dermal absorption 100%

TOXICOKINETIC ASSESSMENT

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration). The substance (NBDI) is insoluble in water, and reacts slowly with water. Therefore, passive diffusion will be limited. In addition, ionization of NBDI will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall. The relatively low molecular weight (206.24) of the substance however indicates that uptake can take place through aqueous pores. It is likely that uptake will be enhanced by local damage caused by the irritating properties of the substance. Overall, it is likely that NBDI is absorbed from the gastro-intestinal tract. For risk assessment purposes oral absorption of NBDI is set at 100%, due to the irritating properties of the substance, leading to potentially damaged gastrointestinal wall. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Once absorbed, distribution of the substance throughout the body is expected based on its relatively low molecular weight. Absorbed NBDI might undergo conjugation. The conjugates will either be excreted via the bile (high molecular weight compounds) or the urine (low molecular weight compounds).

The low vapour pressure (0.02076 Pa) and high boiling point indicates that is not likely that NBDI will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region. However, if the substance reaches the tracheobronchial region, it is likely to be absorbed through the aqueous pores due to the low molecular weight (206.24). In addition, the reactivity of NBDI with water is favourable for absorption. For risk assessment purposes the inhalation absorption of NBDI is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

NBDI, being a liquid, has the potential to partition from the stratum corneum into the epidermis. Since the substance reacts with water and has irritating properties, significant dermal uptake is likely due to damaged skin. As the data are insufficient to meet the criteria for 10% dermal absorption as given in Endpoint specific Guidance (MW> 500 and log Pow <-1 or >4), 100% dermal absorption of NBDI is proposed for risk assessment purposes.

 

Conclusions:

For risk assessment purposes: oral absorption 100%, inhalation absorption 100% and dermal absorption 100%.

Description of key information

For risk assessment purposes the dermal, oral and inhalation absorption is set at 100%

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

TOXICOKINETIC ASSESSMENT

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration). The substance (NBDI) is insoluble in water, and reacts slowly with water. Therefore, passive diffusion will be limited. In addition, ionization of NBDI will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall. The relatively low molecular weight (206.24) of the substance however indicates that uptake can take place through aqueous pores. It is likely that uptake will be enhanced by local damage caused by the irritating properties of the substance. Overall, it is likely that NBDI is absorbed from the gastro-intestinal tract. For risk assessment purposes oral absorption of NBDI is set at 100%, due to the irritating properties of the substance, leading to potentially damaged gastrointestinal wall. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Once absorbed, distribution of the substance throughout the body is expected based on its relatively low molecular weight. Absorbed NBDI might undergo conjugation. The conjugates will either be excreted via the bile (high molecular weight compounds) or the urine (low molecular weight compounds).

The low vapour pressure (0.02076 Pa) and high boiling point indicates that is not likely that NBDI will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region. However, if the substance reaches the tracheobronchial region, it is likely to be absorbed through the aqueous pores due to the low molecular weight (206.24). In addition, the reactivity of NBDI with water is favourable for absorption. For risk assessment purposes the inhalation absorption of NBDI is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed inhalation absorption factor.

NBDI, being a liquid, has the potential to partition from the stratum corneum into the epidermis. Since the substance reacts with water and has irritating properties, significant dermal uptake is likely due to damaged skin. As the data are insufficient to meet the criteria for 10% dermal absorption as given in Endpoint specific Guidance (MW> 500 and log Pow <-1 or >4), 100% dermal absorption of NBDI is proposed for risk assessment purposes.

 

Discussion on absorption rate:

The substance being a liquid has the potential to partition from the stratum corneum into the epidermis. Since the substance reacts with water and has irritating properties, dermal uptake is likely. As the data are insufficient to meet the criteria for 10% dermal absorption as given in the Endpoint specific Guidance (MW> 500 and log Pow <-1 or >4), 100% dermal absorption is proposed for risk assessment purposes.