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EC number: 939-657-1 | CAS number: -
This study does point to a non-specific (irritant) and to a specific immunostimulating (sensitizing) potential of the test item. This applies to NMRI mice, for weight and cell counts of the draining lymph nodes as well as ear swelling and ear weight indices evaluated after application of the test substance.
Compared to vehicle treated animals there were clear increases regarding the weights of the draining lymph nodes and the cell counts, which are of statistical significance in all dose groups. The "positive level" of index 1.4 for the cell counts has been exceeded in all dose groups. (Weight index: 1.0 (0%), 2.07 (10%), 2.41 (30%), 2.18 (100%); Cell count index: 1.00 (0 %) / 2.31 (10 %) / 2.45 (30 %) / 2.90 (100 %).)
The "positive level" of ear swelling which is 2x 10exp-2 mm increase, i.e. about 10 % of the control values, has been exceeded in all dose groups. These changes are of statistical significance. (Ear swelling: day 1 = 17.17 (0 %) / 17.25 (10 %) / 17.25 (30 %) / 17.75 (100 %); day 4 = 17.50 (0 %) / 24.50 (10 %) / 26.42 (30 %) / 27.17 (100 %); Index day 4 = 1.00 (0 %) / 1.4 (10 %) / 1.51 (30 %) / 1.55 (100 %).)
A significant increase compared to vehicle treated animals regarding ear weights was detected in all dose groups. (Ear weight = 11.78 (0 %) / 16.92 (10 %) / 18.28 (30 %) / 18.18 (100 %); Index day 4 = 1.00 (0 %), 1.44 (10 %), 1.55 (30 %), 1.54 (100 %)).
Differentiation indices (DI), which is the quotient of the relative lymph node reaction divided by the relative acute skin reaction was < 1 for all concentrations tested, i.e. 0.82, 0.71 and 0.86 (for calculation of DI see: Homey et.al., Toxicol. and Appl. Pharmacol. 153, 1998, 83 -94; Vohr et.al. Arch. Toxicol. 73, 2000, 501 -509). These DI values point to an irritating potential of the test item. However, such an irritant property could also be combined with a skin sensitizing potential of a test compound. Thus, a skin sensitizing property cannot be excluded.
The body weights of the animals were not affected by any treatment.
A modified LLNA (IMDS; OECD TG 429) was performed on 6 female NMRI mice per dose group using test substance of 0 % (vehicle control), 10 %, 30 % and 100 %.
Compared to vehicle treated animals clear increases regarding the weights of the draining lymph nodes and the cell counts were seen. The "positive level" of index 1.4 for the cell counts has been exceeded in all dose groups.
The "positive level" of ear swelling has also been significantly exceeded and a significant increase regarding ear weights was detected. These changes were of statistical significance in all dose groups. An increase in these parameters would point to an acute irritating (inflammatory) response. However, such an irritant property could also be combined with a skin sensitizing potential of a test compound. Thus, a skin sensitizing property cannot be excluded.
Also it is not possible to calculate an exact EC value from the data obtained, it can be assumed that the EC value is in any case below 10%.
Summarizing, the study does point to a non-specific (irritant) and to a specific immunostimulating (sensitizing) potential of the test item.
The "positive level" of ear swelling has also been significantly exceeded and a significant increase regarding ear weights was detected. These changes were of statistical significance in all dose groups. An increase in these parameters would point to an acute irritating (inflammatory) response. However, such an irritant property could also be combined with a skin sensitising potential of a test compound. Thus, a skin sensitising property cannot be excluded.
For respiratory sensitisation a read across to a substance with a similar chemical composition (HDI oligomerisation product, isocyanurate type, EC No. 931 -274 -8, CAS No 28182 -81 -2) is applied. The read across is based on physicochemical and toxicological similarity of the two substances. Especially a recent comparative pulmonary irritant potency study according to TRGS 430 (Technical Rule for Hazardous Substances 430; published by the German Federal Ministry of Labour and Social Affairs, 2009) confirmed for HDI oligomerisation product, allophanate-type the same toxicological mode of action (irritant portal of entry toxicity) with a similar potency (NOAEC for pulmonary irritation: 3.4 mg/m³ for HDI oligomerisation product, allophanate-type versus 3.3 mg/m³ for HDI oligomerisation product, isocyanurate type). For further justification of the grouping and read-across according to regulation (EC) No 1907/2006, Annex XI, 1.5 see document attached to chapter "Assessment Reports".
The read-across substance (EC No. 931 -274 -8; with residual content of monomeric HDI < 0.2%) revealed no respiratory sensitising potential in two studies with guinea pigs. No specific immediate or delayed effects were observed in a study with respirable aerosolised test substance for induction (5 x 3 hours) and first challenge (both head/nose only exposure), as well as for second challenge with respirable aerosolised test substance-guinea pig-albumin-conjugate. Also no specific immediate or delayed effects were observed in a second study with respirable substance aerosol-challenge (head/nose only exposure), following an induction with 3 consecutive intradermal injections. There are no data available yet regarding the respiratory sensitisation potential in the more sensitive repeated challenge Brown Norway rat bioassay (for reference and discussion see Pauluhn et. al., Experimental and Toxicologic Pathology 56, 2005, 203 -234; Pauluhn et. al., Inhalation Toxicology 17, 2005, 67 -78; Boverhof et. al., Toxicology and Applied Pharmacology 226, 2008, 1 -13). Diisocyanates in general are known respiratory sensitisers in humans. For none of the HDI oligomerisation products respective data are available in humans.
According to Regulation (EC) No 1272/2008, Annex I, the substance has to be classified as Skin Sens 1 (H317: May cause an allergic skin reaction).
No classification required for respiratory sensitisation according to Regulation (EC) No 1272/2008, Annex I, since the existing animal data indicate no sensitisation potential and no respective data are available for humans.
Regulation (EU) No 286/2011, amending Regulation (EC) No 1272/2008, states that, where data are sufficient, a refined evaluation allows the allocation of skin sensitiser into sub-category 1A, strong sensitisers, or sub-category 1B, other skin sensitisers. Where data are not sufficient a classification as Skin Sensitisation Category 1 without sub-categorisation applies.
HDI oligomerisation product, allophanate type is among the substances that are registered under CAS no 28182-81-2 (CAS name:Hexane, 1,6-diisocyanato-, homopolymer; in short: HDI homopolymers). HDI derived homopolymers, like HDI oligomerisation product, uretdione type, isocyanurate type, iminooxadiazindione type and biuret type (all CAS no 28182 -81 -2), that are composed solely by different oligomerisation products of 1,6-hexamethylene diisocyanate monomer, were considered to have a similar skin sensitisation potential. This is based on structural analogy, on similar physico-chemical properties (vapour pressure, viscosity, hydrolytically unstable, reactive with nucleophiles) and on results of in vivo skin sensitisation assays of the substances. Consequently, all of these substances should be allocated to the same category/sub-category for skin-sensitisation. A full and detailed justification concerning the classification of these HDI homopolymers is available and attached to this endpoint summary. Regarding HDI oligomerisation product, allophanate type, although having a slightly different composition (oligomerisation product of HDI and minor amounts of alcohol), allophanate-type HDI oligomerisation product is also member of CAS no 28182-81-2 and should also be allocated to the same category/sub-category for skin sensitization. This is based on the similarity of physico-chemical properties, but also on the assumption and experience that the structural difference resulting from the alcohol will not influence predominantly the skin sensitization potential of the substance.
Here in brief the rationale for the categorization of HDI homopolymers for skin sensitisation:
The classification criteria of Regulation (EU) No 286/2011 cover human as well as animal data. For HDI homopolymers conclusive human data on skin sensitisation are not available (Abschlussbericht zum Forschungsvorhaben FP 272, IVDK, Göttingen, September 2011), which could be partly ascribed to the instability of the test preparations (Frick et. al., Contact Dermatitis 51, 73-78, 2004). Few publications point to human experience with positive patch test reactions indicating skin sensitization (Aalto-Korte et. al., Contact Dermatitis 63, 357-363, 2010), but this seems not to be a very frequent observation.
For HDI monomer, the precursor of HDI homopolymer, no sub-categorisation is currently concluded, since limited data on potency and inconsistent human and animal data does not allow a clear discrimination. Taking into account the database on HDI monomer a sub-categorisation of HDI homopolymers as 1A (strong sensitiser) based on worst case conclusion from the animal data with (some) HDI homopolymers seems not to be adequate and proportionate, since the less reactive HDI homopolymers are not assumed to be the more potent skin sensitisers than the respective monomer. Indeed, scientific evidence exists for some time that chemical reactivity or, more precisely, protein reactivity is linked to the potency of skin sensitisation (Lepoittevin et. al., Allergic Contact Dermatitis: The Molecular Basis. Springer, Berlin, 1998).
Overall, in a weight of evidence approach based on limited data on human experiences and inconsistent animal data as well as based on a comparison of the available data with HDI monomer it is concluded that the available data for HDI homopolymers currently do not allow a solid assessment of the potency. Therefore according to Regulation (EU) No 286/2011, 18.104.22.168.1.1 (“Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation") HDI homopolymers, and also allophanate-type HDI oligomerisation product, should be currently classified in Category 1, without further sub-categorization.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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