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Toxicological information

Respiratory sensitisation

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Administrative data

Endpoint:
respiratory sensitisation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Fully reported study, No guideline available

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 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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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/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:
Intradermal injection or topical application of MDI induces in a proportion of guinea pigs specific antibody responses and pulmonary hypersensitivity. The differences in immunogenicity observed clearly reflect variation in exposure route rather than the concentration of MDI used for sensitisation. The route of exposure influences the effectiveness of sensitisation to respiratory allergens such as MDI, and skin contact may be an important cause of occupational respiratory allergy.