1,3-Butanediol, reaction products with 1,1'-methylenebis[4-isocyanatobenzene], propylene glycol and tripropylene glycol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Justification for type of information:

Hypothesis: Reactive NCO groups present on the substances of the MDI category polymerize in the acid environment of the stomach to form solid polyureas that are excreted via the feces without being absorbed. Consequently, oral exposure does not lead to local or systemic toxic effects.

Justification: All available oral toxicity data indicates consistent lack of toxicity within the data matrix. Further, since the formation of inert polyureas in the acids of the stomach is dependent on the presence of reactive NCO groups and all MDI substances acting via this common mechanism contain high levels of such groups, the mechanism of action justifies the claim of overall consistency within the matrix with high confidence.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

1,1’-Methylenebis(4-isocyanatobenzene) and its reaction products with [(methylethylene)bis(oxy)]dipropanol, butane-1,3-diol and propylene glycol

EC Number:

941-496-7

Cas Number:

1689576-89-3

Molecular formula:

C14 H10 NO (C15 H12 N2 O2 R)n NCO where R = C4 H8 O2 and C9 H18 O4 and C3 H6 O2, n = 0-2

IUPAC Name:

1,1’-Methylenebis(4-isocyanatobenzene) and its reaction products with [(methylethylene)bis(oxy)]dipropanol, butane-1,3-diol and propylene glycol

Results and discussion

Effect levels

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Remarks on result:

other: Weight of evidence was performed on a sufficient representation of category and sub-category substances to demonstrate the lack of a trend in the data and to conclude a lack of acute oral toxicity across the substances of the MDI category.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

No acute oral data exist for 44MDI/1,3-BD/TPG/PG. Accordingly, this endpoint is satisfied by a weight of evidence and read-across from valid acute oral toxicity studies on category substances that are considered the worst-case according to the hypothesized MoA. The study used (Bomhard, 1990) for read-across did not record mortality up to the limit dose of 2,000 mg/kg bw when rats were administered MDI mixed isomers. Both 2,4’-MDI and MDI mixed isomers are both member of the monomeric MDI subgroup.
Acute oral toxicity studies have been performed on a sufficient representation of category and sub-category substances (see table 1. attached background material) to demonstrate the lack of a trend in the data and to conclude a lack of acute oral toxicity across the substances of the MDI category. Based on the available study data all members of the MDI category are regarded as relatively non-toxic for the endpoint acute oral toxicity and are not classified according EU GHS 1272/2008 CLP.

Executive summary:

The available data indicate that all substances of the MDI category are of low toxicity by the oral route. Following acute oral exposure, the NCO groups present on the substances of the MDI category react with acids within the stomach leading to formation of an insoluble polymerized mass that is excreted in the feces without being absorbed. Acute oral toxicity studies performed on a sufficient representation of category substances define a lack of acute oral toxicity across the category.

The available acute oral toxicity studies are of high reliability and are sufficient for demonstrating the acute oral toxicity of the substances of the MDI category. Reliable chemical composition including NCO content is also available for all substances of the MDI category acting via this common mechanism and provides an adequate basis for predicting read-across between all of them.

All substances of the MDI category share similar chemical features namely that they a) all contain a significant amount of mMDI, and b) contain at least two NCO functional groups per molecule which is bound to an aromatic ring and this ring is connected to a second aromatic ring by a methylene group. It is the NCO value (driven by the bioaccessible groups on monomeric MDI and low molecular weight constituents (e.g. three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As reactive NCO groups are a common feature of all substances of the MDI category, it is predicted that these have a similar reactivity profile and a read across within the category is warranted (detailed information on the Mode of Action is available in Category Justification Document).

This low toxicity is consistent with the overall hypothesis:  a) the bioaccessible reactive NCO group drives chemical and biological activity, and b) MDI substances are not systemically absorbed because the NCO groups present on them react with acids within the stomach leading to the formation of an insoluble polymerized mass that is excreted in the feces without being absorbed.