Registration Dossier

Diss Factsheets

Toxicological information

Respiratory sensitisation

Currently viewing:

Administrative data

Endpoint:
respiratory sensitisation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
Hypothesis: Available NCO groups present on the substances react readily with nucleophilic groups such as amines, thiols and alcohols, the primary reaction partner in the epithelial lung fluid being glutathione. Subsequent transcarbamoylation from GSH to a protein, or direct reaction of NCO with a protein, marks antigen formation and the MIE of the sensitization process. Upon re-exposure via the respiratory route, protein-hapten complexes are recognized by the immune system, triggering an immunological response resulting in the induction of sensitization. Therefore, as the MIE is driven by the NCO groups on MDI substances, NCO reactivity with biological nucleophiles is the critical chemical reaction that drives the sensitization response and has been demonstrated for worst-case boundary substances (4,4’-MDI and pMDI). All category substances containing bioaccessible NCO will be classified as respiratory sensitizers.
Justification: Although there are no guidelines available for respiratory sensitization studies in animals, several researchers have shown respiratory changes in animals after induction exposure and subsequent challenge with both 4,4’-MDI and pMDI. The studies showed some type of respiratory response (alterations in respiratory rate, non-specific hyperreactivity, influx of inflammatory cells), however differences in immunogenicity observed clearly reflect variation in induction exposure route and/or challenge concentration. Attempts to sensitize guinea pigs by single inhalation exposure only to 4,4’-MDI showed borderline responses at best as compared with potent respiratory sensitizers such as ovaalbumin and trimellitic anhydride. Respiratory responses were only provoked in animals challenged with overtly irritant concentrations of 4,4’-MDI or pMDI. For an overview of respiratory sensitization data across the category members, see attached table under "overall remarks, attachments".
For more details see category justification document attached in IUCLID section 13 and field “Executive Summary” below.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994
Reference Type:
publication
Title:
Unnamed
Year:
1994

Materials and methods

Test material

Constituent 1
Reference substance name:
1,1'-Methylenebis(4-isocyanatobenzene) and oligomeric reaction products of 1,1'-methylenebis(4-isocyanatobenzene) and oxydipropanol and oligomerization reaction products of oxydipropanol
EC Number:
701-041-3
Molecular formula:
C14 H10 N O [C21 H24 N2 O5]n N C O with n=0, 1, 2, 3
IUPAC Name:
1,1'-Methylenebis(4-isocyanatobenzene) and oligomeric reaction products of 1,1'-methylenebis(4-isocyanatobenzene) and oxydipropanol and oligomerization reaction products of oxydipropanol

Results and discussion

Results:
Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful. No animals exhibited pulmonary responses following challenge with atmospheric MDI. In contrast, a proportion of animals exhibited pulmonary responses following inhalation challenge after induction by intradermal injection or topical application

Any other information on results incl. tables

GROUP

% MDI

PULMONARY RESPONSES

PCA

Topical 1

0

0/8

0/8

Topical 2

10

2/8

0/8

Topical 3

30

2/8

2/8

Topical 4

100

3/7

2/8

Intradermal 1

0

0/8

0/8

Intradermal 2

0.0003

0/6

0/8

Intradermal 3

0.003

1/8

0/8

Intradermal 4

0.03

5/8

1/8

Intradermal 5

0.3

5/8

3/8

Inhalation 1

0 mg/m3

1/7

0/8

Inhalation 2

19.4-23.7 mg/m3

0/16

0/16

Applicant's summary and conclusion

Interpretation of results:
sensitising
Conclusions:
Based on the available read-across data, the target substance 44MDI/DPG is considered a respiratory sensitizer. This is based on the hypothesis that the respiratory sensitization potential of all MDI category members results from highly reactive NCO groups that react with extracellular biological nucleophiles and cellular proteins. These reactive NCO groups are present in all category substances to significant percentages. Therefore, all category members for which no substance-specific data is available (including 44MDI/DPG) are assigned the CLP classification as respiratory sensitizer (Cat. 1, H334) for 4,4’-MDI.
Executive summary:

No respiratory sensitization data exist for the target substance 44MDI/DPG. This endpoint is satisfied by weight of evidence and read across from two respiratory sensitization studies performed with 4,4’-MDI and pMDI, both belonging to the MDI category. All of the available studies are assigned Klimisch ratings of either 1 or 2.


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 are 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 low molecular weight bioaccessible groups on monomeric MDI and three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As mentioned above, all substances of the MDI category contain a high content of monomeric MDI. This is key to the hypothesised MoA for all substances of the MDI category.


Since it has been demonstrated that NCO value (as attenuated by solubility) is responsible for toxicity and the higher molecular weight, low solubility components do not contribute to the observed toxicity, it is reasonable to assume that their presence in these mixtures diminishes the overall toxicity causing variation in effect. However, as all substances contain sufficient bioaccessible MDI constituents to elicit effects, a worst-case approach is adopted in which the most bioaccessible substances are read across to all substances of the MDI category. Accordingly, the CLP classification (Cat. 1, H334) for 4,4’-MDI is adopted for all other substances in the MDI category, including the target substance 44MDI/DPG.


For more details see category justification document attached in IUCLID section 13.