[No public or meaningful name is available]

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study planned

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 4,4'-MDI/DPG/HMWP

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies: No developmental GLP studies are available on the test substance.
- Available non-GLP studies: No developmental non-GLP studies are available on the test substance.
- Historical human: There are no appropriate historical human data that address developmental toxicity to the test substance.
- (Q)SAR: There are no QSAR models available developmental toxicity endpoint that are sufficiently validated and acceptable.
- In vitro methods: There are no validated tests that use in vitro methodologies that could be used to meet the standard requirement of the REACH regulation for developmental toxicity.
- Weight of evidence: Results of a sub-acute study on the test substance are available along with a well-defined mechanism of action can be used for a weight of evidence evaluation. However, no developmental studies are available on the test substance.
- Grouping and read-across: The substance is part of a grouping category that has a well-defined mechanism of action. A negative developmental toxicity study is already available for the category substances considered the worst case. The current substance is considered the least toxic boundary substance for the MDI substance category and will be used to support read-across for the remainder of the category. An additional OECD 422 will be performed on the registered substance to support category read-across.
- Substance-tailored exposure driven testing [if applicable] – Not applicable
- Approaches in addition to above [if applicable] Not applicable
- Other reasons [if applicable] – Not applicable

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- none of the adaptation possibilities in REACH Annex VIII to X is adequate to generate the necessary information or waive this study. Relevant human exposure cannot be excluded as the substance is used in an industrial setting under non-closed conditions.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION :
The substance is part of a category read-across based on the hypothesized MoA that predicts local effects in the lungs and no significant systemic exposure to unreacted NCO since it reacts with biological nucleophiles before being absorbed as GHS/protein adducts. With no systemic exposure to unreacted isocyanate or toxic metabolite, no effects on developmental toxicity are predicted. This is consistent with the observed lack of systemic toxicity in combined chronic toxicity and carcinogenicity studies on 4,4’-MDI and pMDI as well as the proposed mechanism for MDI absorption toxicokinetics.
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).
However, as no developmental toxicity data from the required test guideline for Annex X is available for the boundary substance considered the least toxic, the current study is proposed (4,4’-MDI/DPG/HMWP) to support the common mechanism. Additional screening studies (OECD 422) will be performed on selected category members from each sub-group to act as bridging studies. These additional studies will confirm that hypothesis that additional structural features to not contribute to the systemic and developmental toxicity and that 4,4’-MDI would still be considered the worst-case substance. If these additional studies suggest additional toxic potential, additional OECD 414 studies will be proposed.
This study will be expected initiated following the completion of an OECD 422 Reproductive toxicity screen that will be used to assist in dose selection. Depending on laboratory capacity, It is expected a report on the OECD 414 will be available approximately 12 months following the initiation of the OECD 422 study.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Test material

Test material information

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:

C8H6NO [C7H5NO [C3H6O]n C8H7NO ]m C7H4NO with 2<=n<20 and 0<=m<=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

Test animals

Species:

rat

Administration / exposure

Details on study design:

- Basis for dose level selection: An existing 28D study is available on the test substance and along with an OECD 422 study which will be performed prior to main study will help select doses for the definitive study. The OECD 422 study will also serve as a basis for comparing bridging studies for multiple category members. In addition, study data from existing sub-chronic and chronic study data will be used for dose selection (Hoymann et al. 1994 for 4,4’-MDI, Reuzel et al. 1994 for pMDI). These supporting studies demonstrate that even with a chronic/lifetime exposure duration with group sizes equivalent to or greater than guideline reproductive studies, effects from pMDI and 4,4’-MDI aerosols are confined to the lungs. Effects on systemic organs including reproductive organs were not observed at exposure concentrations associated with marked respiratory tract toxicity.

- Route of administration: inhalation route
A need for an oral hazard assessment for MDI is not indicated by its use or by toxicokinetic profile of exposure routes. Furthermore, oral toxicity data for MDI cannot be extrapolated for risk assessment of inhaled aerosols as the relevant route of exposure for human risk assessment. Therefore, there is no apparent benefit from any oral toxicity data for MDI. Toxicokinetic data for the inhalation route of exposure is sufficient, and the performance of an additional oral animal toxicity study would not create data that would influence the risk management measures and therefore would be in conflict with the principles of animal use and welfare. These differences are described below:

Route of exposure specific differences in MDI metabolism

4,4’-MDI (MDI) contains two highly reactive NCO-groups, which are responsible for the distinct portal of entry toxicity described by the available toxicological data. The NCO-group reacts readily with nucleophilic biomolecules, and depending on the chemical and physico-chemical composition of the interphase at the site of primary contact, distinct differences in primary reaction products can be described. Therefore significant differences in bioavailability and metabolic fate can be described for the oral, dermal and inhalation route of exposure (see end point summary on toxicokinetics\):
• in the pH neutral medium of the lung inhaled respirable MDI aerosols react with the proteins and peptides (mainly glutathione) of the bronchioalveolar fluid, partly representing bioavailable adducts,
• direct intubation of large MDI doses into the stomach is an artificial exposure route and can only simulate accidental swallowing. In the acidic pH of the stomach MDI polymerizes with the stomach content and forms solid and inert polyureas. Information from analogous diisocyanates and US reports on accidental ingestion of MDI based glues in domestic animals describe formation of high molecular primary reaction products with CO2 liberation, without apparent systemic chemical toxicity. Polymeric reaction products are of low bioavailability.
• Following oral swallowing of traces of MDI, reactions will commence at once with biological macromolecules in the buccal region and will continue along the oesophagus prior to reaching the stomach. Reaction products will be a variety of polyureas and macromolecular conjugates with for example mucus, proteins and cell components.
• at the interface of the skin, reactions with nucleophilic groups of the skin matrix and polymerization to a solid polyurea crust occurs, significantly reducing bioavailability. (Based on this knowledge it should only be speculated on the effects of an agglutination of the reactive MDI with blood proteins following i.v. application.)

In conclusion the toxicokinetic behaviour of MDI needs to be considered with respect to the specific physico-chemical and chemical exposure conditions at the site of first contact. For MDI, significant differences in primary reaction products and by this in the subsequent bioavailability and metabolic fate imply a high level of uncertainty for route to route extrapolation of toxicological data. In accordance to REACh Annex I (0.3.), the chemical safety assessment of a substance shall be based on a “…known or reasonably foreseeable exposure…”, accidental exposures are not considered. Therefore, and in accordance to ECHA Guidance Chapter R.7a and the REACh Annexes on information requirements the potential hazard of MDI should be determined on the most relevant route of exposure for risk assessment which is inhalation.

Relevance of oral route of exposure for risk and hazard assessment:
ECHA Guidance Chapter R.14 (Occupational exposure estimation, R.14.2 Types and routes of exposure) indicates that, exposure through ingestion is “…generally not considered further in the assessment of workplace exposure“. For proof of concept, working processes for professional uses of MDI include handling and spray application of foams in concentrations up to max 30 % pbw. Other uses include handling and application of coatings, adhesives and paints in which MDI is not contained as such but as pre-reacted high viscous polymer with low monomer content. For spray applications in which aerosols are generated respiratory protection by full mask, and for all application’s effective dermal protection by full body protection and gloves is prescribed. These risk reduction measures effectively prevent from any oral exposure, e.g. via contaminated skin or clothing or inhalation cross-contamination. Cured PU applications, e.g. spray foam, do not contain residual unreacted MDI (see Topic 6 below). In conclusion, no significant uncertainties regarding a potential oral exposure can be anticipated in the holistic exposure assessment for professionals.

ECHA Guidance Chapter R.15 (Consumer exposure estimation, R.15.2.2 Reasonable worst-case situations) indicates that, “…the consumer exposure estimation should normally address the intended uses of the products that contain the substances under investigation. However, since consumers may not accurately follow instructions for use of products, an estimation of other reasonably foreseeable uses should be made. Consideration of deliberate abuse is not part of the exposure estimation process.” Consumer uses include one component rigid foam available in cans as well as coatings, adhesives & sealants, and paintings. These uses contain pre-reacted and polymerized MDI derivatives (prepolymers and higher oligomers originating form polymeric MDI (PMDI)) with low amounts of residual monomer. Reaction is readily with humidity in the air, resulting in entirely cured product, free of residual MDI.

Consumer uses of MDI are covered by national regulations, which e.g. restrictively prescribe selling in correspondingly equipped DIY stores, if the consumer agrees to information provided by the staff addressing the risk. In addition, the appropriate storage and handling is explicitly prescribed, e.g. by the recommendation to use gloves which are delivered with every can as part of an existing restriction under REACH Annex XVII as follow up of the 2005 Risk Assessment. Therefore, there is a very low possibility for oral exposure by the intended use, since e.g. skin contact should be prevented by the use of gloves, and by this dermal to oral cross-contamination is minimized. Since cured PU applications, e.g. spray foam, do not contain residual unreacted MDI (see Appendix 1 on Toxicological information, DNEL justification provided as a separate document) migration from articles through sucking, chewing or licking can likewise be excluded. In addition, no foreseeable misuse other than abuse has to reasonably be anticipated due to specific regulations of the consumer application.

- Other considerations, e.g. on choice of species, strain, vehicle and number of animals [if applicable]: Wistar rats will be used as the species as they have been extensively used in MDI substances and provide an appropriate basis for comparison between studies.