Isocyanic acid, polymethylenepolyphenylene ester, 2-ethyl-1-hexanol-blocked

Respiratory sensitisation

Administrative data

Endpoint:

respiratory sensitisation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Fully reported study, No guideline available

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

1994

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

No guideline for respiratory sensitisation is validated.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-methylenediphenyl diisocyanate

EC Number:

202-966-0

EC Name:

4,4'-methylenediphenyl diisocyanate

Cas Number:

101-68-8

Molecular formula:

C15H10N2O2

IUPAC Name:

1,1'-methylenebis(4-isocyanatobenzene)

Constituent 2

Reference substance name:

benzene, 1,1'- methylenebis[4-isocyanato-

IUPAC Name:

benzene, 1,1'- methylenebis[4-isocyanato-

Details on test material:

SOURCE: ICI polyurethanes, Belgium
PURITY: monomeric 4,4'-MDI
HAPTEN-PROTEIN CONJUGATE: conjugate of 4,4'-MDI with guinea pig serum albumin (GPSA; Sigma
Chemical Co., St. Louis, MO)

Test animals

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Porcellus Animal Breeding, Sussex, UK
- Weight at study initiation: 250-300g
- Housing: individually
- Diet (e.g. ad libitum): ad libitum except during inhalation exposure periods
- Water (e.g. ad libitum):ad libitum except during inhalation exposure periods
- Acclimation period: at least 10 days

Test system

Route of induction exposure:

other: groups were exposed by intradermal injection, topical application, or inhalation exposure

Route of challenge exposure:

inhalation

Vehicle:

other: corn oil only in i.d. and topical exposures

Concentration:

Topical induction: Concentration in vehicle: 0, 10, 30, 100 %
Intradermal induction: Concentration in vehicle: 0, 0.0003, 0.003, 0.03, 0.3% of MDI
Inhalation induction: Concentration: between 19.4 and 23.7 mg/m³

Inhalation challenge concentration:
topical sensitisation: 25.9 to 36.4 mg/m³;
intradermal sens.: 27.6 to 36.5 mg/m³;
inhalation sens.: 34.6 to 44.1 mg/m³

No. of animals per dose:

topical: 4 groups, n=8;
intradermal: 5 groups, n=8;
inhalation: n=16

Details on study design:

MAIN STUDY
A. INDUCTION EXPOSURE
1. Topical induction
- No. of exposures: 1
- Exposure period: 6 hours under occlusion
- Test groups: 3 Groups of 8 animals
- Control group: 8 animals untreated
- Site: shaved scapular region
- Concentrations: 400 μl of 0, 10, 30, 100 % MDI in corn oil

2. Intradermal induction
- No. of exposures: 1
- Test groups: 4 Groups of 8 animals
- Control group: 8 animals untreated
- Concentrations: 100 μl of 0, 0.0003, 0.003, 0.03, 0.3% of MDI in corn oil

3. Inhalation induction
- No. of exposures: 5
- Exposure period: 3 hours (nose only)
- Test groups: 3 Groups of 8 animals
- Control group: 8 animals exposed to dry air
- Frequency of applications: daily
- Duration: 5 days
- Concentrations: 19.4 and 23.7 mg/m³


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 21
- Exposure period: 15 minutes
- Test groups: all induction groups
- Control group:
- Concentrations: topically induced: 25.9 to 36.4 mg/m³; intradermally induced.: 27.6 to 36.5 mg/m³; inhalation induction: 34.6 to 44.1 mg/m³
- Evaluation : 10 minute baseline monitoring after 15 minute settling period; Monitoring 15 minutes during exposure and 15 minutes after removal from the challenge atmosphere
EXPOSURE ATMOSPHERE:
pre-warmed air was passed over the surface of MDI maintained at 65°C to create a saturated vapour. The MDI vapour was condensed by cooling to form an aerosol, adjusted with air to provide the appropriate atmospheric concentration. Particle size: MMAD ± 1.5 μm
PARAMETERS ASSESSED DURING THE STUDY:
- pulmonary hypersensitivity: measured as changes in respiratory rate following inhalation challenge;
- contact hypersensitivity: measured by topical challenge (modified Magnusson and Kligman; 100 μl of 3% MDI on shaved flanks) and antibody responses: ELISA and Passive Cutaneous Anaphylaxis (PCA). Blood was drawn by cardiac puncture 18 days following the initiation of exposure

Challenge controls:

control group n=7 received induction exposure to dry air and challenge expposure as treated animals

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/m^3	1/7	0/8
Inhalation 2	19.4-23.7 mg/m^3	0/16	0/16

Applicant's summary and conclusion

Interpretation of results:

sensitising

Conclusions:

The current study is a source key study used (Rattray et al. 1994) for read-across to MDI MT and indicates a potential of respiratory sensitization. Also no generally accepted and validated test system is available to investigate the sensitizing effects of substances on the respiratory tract, numerous animal studies are available to demonstrate the respiratory sensitizing potential. Groups of guinea pigs were exposed to 4,4’-MDI by intradermal injection, topical application, or inhalation exposure for induction and by inhalation to 25-44 mg/m3 MDI for the challenge exposure (Rattray et al. 1994). Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful; no animals exhibited pulmonary responses following challenge with MDI. Intradermal injection or topical application of MDI induced specific antibody responses and pulmonary responses in 12-65 % of guinea pigs depending upon induction dose and route. The findings from the guinea pig study, indicating a potential for respiratory sensitization and are in line with findings from other animals studies and observations in humans. 4,4’-MDI is officially classified as respiratory sensitizer (Cat.1) EU GHS 1272/2008 CLP.

Executive summary:

Numerous animal studies are available to demonstrate the respiratory sensitizing potential of MDI, which is supported by clinical observations in humans. For the endpoint respiratory sensitization all effects are consistent with the hypothesized MoA and direct electrophilic reactions of the NCO group on mMDI with biological nucleophiles. 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.

As the source substance 4,4’-MDI and the target substance MDI MT contain sufficient monomeric MDI, the driver of toxicity, similarities in reactions leading to respiratory sensitization are assumed. Accordingly, the CLP classification (Cat. 1, H334) for 4,4’-MDI is adopted to the target substance MDI MT.