1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Hypothesis: In the case of dermal exposure, before the reactive NCO groups present on MDI substances have opportunity to be absorbed to any significant extent through the stratum corneum they react with proteins and moisture at the skin surface leading to the formation of an insoluble polymerized mass thereby limiting dermal absorption and systemic availability. Modified MDI substances, having a higher molecular weight than mMDI isomers and due to their higher molecular volume, increased octanol-water partition coefficient and decreased water solubility will in any event not be able to penetrate the stratum corneum.

Justification: Considering that there is only data available for two substances of the MDI category this is insufficient to serve as the sole basis for concluding consistency of effects within the data matrix. However, since the formation of inert polyureas is dependent on the presence of reactive NCO groups and all substances acting via this common mechanism contain high levels of such groups, this justifies the claim of consistency within the matrix with high confidence.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1964

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol

EC Number:

701-173-1

Molecular formula:

C14 H10 NO (C15 H12 N2 O2 R)n NCO where R = C4 H8 O2 and C4 H8 O3 and C3 H6 O2, n=0-2

IUPAC Name:

1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol

Results and discussion

Effect levels

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 9 400 mg/kg bw

Remarks on result:

other: Weight of evidence, Based on the available study data all members of the MDI category are regarded as relatively non-toxic for the endpoint acute dermal toxicity and

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

No acute dermal data exist for the target substance 44MDI/1,3-BD/DEG/PG. Accordingly, this endpoint is satisfied by a weight of evidence and read-across from valid acute oral toxicity studies on category substances . The study used (Wazeter et al. 1964) ) for read-across did not find lethality up to the maximum dose tested, and the LD50 was greater than 9,400 mg/kg bw (Wazeter et al., 1964a). A lack of acute dermal toxicity is confirmed by the available acute dermal toxicity studies of the MDI category (see table attached background material). Based on the available study data all members of the MDI category are regarded as relatively non-toxic for the endpoint acute dermal toxicity and are not classified according EU GHS 1272/2008 CLP.

Executive summary:

The available acute dermal toxicity studies indicate that all substances of the MDI category have low acute dermal toxicity. The study describing the acute dermal toxicity of pMDI in rabbits did not find lethality up to the maximum dose tested, and the LD50 was greater than 9,400 mg/kg bw (Wazeter et al., 1964a). Other less reliable studies on pMDI or 4,4’-MDI are consistent with this.  Observed differences in LD50 values between pMDI and 4,4'-MDI/TPG are not considered to be significant or represent a trend since they are significantly higher than the limit for classification and are indicative of a lack of systemic exposure. The available data for the substances of the MDI category is consistent with the hypothesis that NCO groups present on MDI substances react with proteins and moisture at the skin surface leading to the formation of an insoluble polymerized mass resulting in limited dermal absorption and systemic availability. The available data and hypothesis is supported by the key dermal absorption study that shows that MDI substances have very low systemic bioavailability (<1 %) (Leibold et al., 1999). By comparison, modified MDI substances, with molecular weight greater than mMDI, will

demonstrate even further reduced dermal absorption based upon physico-chemical properties (i.e. increased octanol-water partition coefficient, decreased water solubility, and increased molecular weight), and this has been confirmed with GastroPlus™ modeling (Bartels, 2021). Although a reliable, acute dermal in vivo toxicity data is only available on two category substances, it is considered sufficient for assessment of this endpoint for the category.

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).