1,3-bis(isocyanatomethyl)benzene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: theoretical approach

Adequacy of study:

key study

Study period:

N/A

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Toxicokinetic assessment by a certified toxicologist based on the available information.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, May 2008

Deviations:

not applicable

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,3-bis(isocyanatomethyl)benzene

EC Number:

222-852-4

EC Name:

1,3-bis(isocyanatomethyl)benzene

Cas Number:

3634-83-1

Molecular formula:

C10H8N2O2

IUPAC Name:

1,3-bis(isocyanatomethyl)benzene

Details on test material:

- Name of test material (as cited in study report): XDI
- Physical state: liquid

Results and discussion

Main ADME results

Type:

absorption

Results:

For risk assessment purposes: oral absorption 50%, inhalation absorption 100% and dermal absorption 100%

Any other information on results incl. tables

TOXICOKINETIC ASSESSMENT

As XDI is a diisocyanate, it reacts with water. Isocyanates hydrolyze readily in water to yield a carbamic acid, which decarboxylates to produce CO2 and an amine; the latter can immediately react with more isocyanate to yield a disubstituted urea. The hydrolysis rate increases with electron-withdrawing substituents. Steric hindrance also influences hydrolysis rate. Even at low pH, a hydrolysis Half-Life < 10 minutes (25°C) has been found for isocyanates. Physicalchemical characteristics of XDI requiring studies in aqueous surroundings (as water solubility, octanol/water partition coefficient and surface tension) can therefore not be determined on XDI

itself. The short hydrolysis half-life indicates that the parent compound may only be present in the GI-tract for a limited period of time. Hence, toxicokinetic predictions based on the characteristics of the parent compound may be of limited relevance. As human absorption of a substance always requires contact with aqueous solutions, it is concluded that any uptake of XDI will be very limited (1, 3).

When considering the values for water solubility and partition coefficient as determined for the CSA, it is anticipated that the relative small molecular size (<200) and the moderate log Pow (between 0 and 4) of XDI are favourable for absorption, whereas the relatively low water solubility (106.27 mg/L) is not favourable for absorption by the GI-tract. Based on these physicochemical properties of XDI, a moderate uptake by the GI-tract is anticipated, and for risk assessment purposes the oral absorption of XDI is set at 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption percentage.

After absorption, XDI will react with water as stated above, yielding carbamic acid, CO2, amine and disubstituted urea. Because of the relative small molecular weight of XDI, the hydrolysis products and/or metabolites will either be excreted via the bile or the urine.

Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The low vapour pressure of the substance (0.0206 Pa) indicates that the substance will not be available for inhalation as vapour. The relatively low water solubility is favourable for penetration to the lower respiratory tract (2). Based on these physico-chemical properties of XDI, for risk assessment purposes the inhalation absorption is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed inhalation absorption percentage.

XDI, being a liquid, has the potential to be dermally absorbed. The moderate log Pow of 3.07 is also indicative of dermal absorption. The criteria for 10% dermal absorption as given in the Reach Guidance on information requirements and chemical safety assessment (2) (MW>500 and log Pow is outside of the range -1 to 4) is not met, and therefore 100% dermal absorption of XDI should be considered for risk assessment purposes. Although it is generally accepted that dermal absorption is not higher compared to oral absorption, 100% dermal absorption should be considered for risk assessment purposes as XDI has skin irritating properties and damage to the skin surface may enhance penetration.

REFERENCES

1. Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

2. Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, May 2008.

3. A. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001.

Applicant's summary and conclusion

Conclusions:

For risk assessment purposes the following absorption factors were derived: oral absorption factor: 50%; dermal absorption factor: 100%; inhalation absorption factor: 100%