Reaction mass of 2-Ethylhexyl N-(5-isocyanato-2-methylphenyl)carbamate and 2-Ethylhexyl N-(3-isocyanato-4-methylphenyl)carbamate and N,N'-(4-Methyl-1,3-phenylene)bis(carbamic acid) C,C'-bis(2-ethylhexyl) ester

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

14 December 2009

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Result predicted by calculation.

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Principles of method if other than guideline:

A structural activity relationship analysis was conducted using Derek for Windows (Lhasa Ltd., UK).

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of 2-Ethylhexyl N-(5-isocyanato-2-methylphenyl)carbamate and 2-Ethylhexyl N-(3-isocyanato-4-methylphenyl)carbamate and N,N'-(4-Methyl-1,3-phenylene)bis(carbamic acid) C,C'-bis(2-ethylhexyl) ester

EC Number:

937-955-6

Molecular formula:

components with the molecular formulae C25H42N2O4 and C17H24N2O3

IUPAC Name:

Reaction mass of 2-Ethylhexyl N-(5-isocyanato-2-methylphenyl)carbamate and 2-Ethylhexyl N-(3-isocyanato-4-methylphenyl)carbamate and N,N'-(4-Methyl-1,3-phenylene)bis(carbamic acid) C,C'-bis(2-ethylhexyl) ester

Results and discussion

Any other information on results incl. tables

Results

When the structure was compared against the DEREK for Windows structure database, with tautomers and both implicit and explicit hydrogens included, there were five alerts:

 

-010 Isocyanate. Respiratory sensitisation.

-211 Isocyanate. Irritation (of the respiratory tract), Irritation (of the eye), Irritation (of the skin).

-304 Isocyanate or isothiocyanate. Mutagenicity, Chromosome damage.

-308 Alkyl carbamate. Chromosome damage.

-409 Isocyanate. Skin sensitisation.

 

There is a long history of occupational exposure to isocyanates resulting in respiratory and skin sensitisation, and irritation of respiratory tract, eye and skin. These compounds are highly reactive and frequently are very volatile which creates a situation in which irritation or sensitisation of the lung may occur. However, even the less volatile compounds may reach concentrations sufficient to cause irritation or sensitisation.

 

Irritation and sensitisation are greatly affected by physical parameters. Volatility will affect the respiratory tract. Skin penetration is favoured by relatively lipophilic molecules (Log P (octanol/water) = 1 - 4) of low molecular weight (<500). The Log P and molecular weight for the test material are 5.996 and 304.39 respectively. For many classes of chemicals (e.g. aliphatic amines) eye irritation is greatest for the more water soluble compounds which readily dissolve in the aqueous tear film on the cornea and conjunctiva. Liquid substances (cf. solids) have good tissue contact that promotes surface penetration and reactivity.

 

DEREK has indicated that irritation and sensitisation are plausible in humans. In the absence of further testing, the physical structure of the test material and the long history of toxicity due to isocyanates, supports the DEREK statement that such reactions are plausible.

 

Some alkyl carbamates are known to cause chromosome damage in vitro, with the primary example being ethyl carbamate. It goes through two biotransformations resulting in vinyl carbamate epoxide. It is this reactive epoxide which can cause chromosomal damage. Whether or not the test material will be metabolised to an epoxide will likely be affected by size and steric hindrance. DEREK has indicated that chromosome damage is plausible; in the absence of further testing this seems a reasonable conclusion. The data on mutagenicity and chromosome damage due to isocyanate exposure are mixed; however, DEREK again has indicated plausibility for this alert, which is reasonable in the absence of specific data on this compound.

Applicant's summary and conclusion

Conclusions:

There were five alerts:

-010 Isocyanate. Respiratory sensitisation.
-211 Isocyanate. Irritation (of the respiratory tract), Irritation (of the eye), Irritation (of the skin).
-304 Isocyanate or isothiocyanate. Mutagenicity, Chromosome damage.
-308 Alkyl carbamate. Chromosome damage.
-409 Isocyanate. Skin sensitisation.

Executive summary:

When the structure of the test material was compared against the DEREK for Windows structure database, with tautomers and both implicit and explicit hydrogens included, there were five alerts:

 

-010 Isocyanate. Respiratory sensitisation.

-211 Isocyanate. Irritation (of the respiratory tract), Irritation (of the eye), Irritation (of the skin).

-304 Isocyanate or isothiocyanate. Mutagenicity, Chromosome damage.

-308 Alkyl carbamate. Chromosome damage.

-409 Isocyanate. Skin sensitisation.

 

There is a long history of occupational exposure to isocyanates resulting in respiratory and skin sensitisation, and irritation of respiratory tract, eye and skin

Irritation and sensitisation are greatly affected by physical parameters. Volatility will affect the respiratory tract. Skin penetration is favoured by relatively lipophilic molecules (Log P (octanol/water) = 1 - 4) of low molecular weight (<500). The Log P and molecular weight for the test material are 5.996 and 304.39 respectively. For many classes of chemicals eye irritation is greatest for the more water soluble compounds which readily dissolve in the aqueous tear film on the cornea and conjunctiva.

DEREK has indicated that irritation and sensitisation are plausible in humans. In the absence of further testing, the physical structure of the test material and the long history of toxicity due to isocyanates, supports the DEREK statement that such reactions are plausible.

 

Some alkyl carbamates are known to cause chromosome damage in vitro, with the primary example being ethyl carbamate. It goes through two biotransformations resulting in vinyl carbamate epoxide. It is this reactive epoxide which can cause chromosomal damage. Whether or not the test material will be metabolised to an epoxide will likely be affected by size and steric hindrance. DEREK has indicated that chromosome damage is plausible; in the absence of further testing this seems a reasonable conclusion. The data on mutagenicity and chromosome damage due to isocyanate exposure are mixed; however, DEREK again has indicated plausibility for this alert, which is reasonable in the absence of specific data on this compound.