4,4'-methylenediphenyl diisocyanate

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: Chronic repeated dose toxicity test

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This is only a short summary of the repeated dose toxicity study related to the reproductive organs, the full study can be found in section 7.5.2

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Principles of method if other than guideline:

Chronic repeated dose toxicity test including macroscopically and gross pathologically assessment of the reproductive organs and tissues.

GLP compliance:

yes

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-isocyanato-4-[(4-isocyanatophenyl)methyl]benzene

Details on test material:

Monomeric 4,4'-methylenediphenyl diisocyanate (Desmodur 44 M Schuppen from Bayer AG, Leverkusen); 13 batches were tested (purity: >99.5 %)

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

See section 7.5.2a Hoymann et al 1995 (rat, 2y)

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

See section 7.5.2a Hoymann et al 1995 (rat, 2y)

Details on mating procedure:

Not included in the test as this is a repeated dose test.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

See section 7.5.2a Hoymann et al 1995 (rat, 2y)

Duration of treatment / exposure:

up to 2 years

Frequency of treatment:

17 hours per day; 5 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.2, 0.7, 2.1 mg/m3
Basis:
nominal conc.

No. of animals per sex per dose:

80 females per dose; at each dose level there were additional 80 rats per group in satellite groups for : chronic toxicity over 12 months (20 animals); lung function over 20 months (12 animals); lung clearance over 20 months (8 animals); bronchoalveolar lavage, biochemistry over 3 months +1 week recovery (20 animals); bronchoalveolar lavage, biochemistry over 12 months + 1 week recovery (20 animals).

Control animals:

yes, sham-exposed

Details on study design:

See section 7.5.2a Hoymann et al 1995 (rat, 2y)

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Full pathological examination was done on 20 rats/dose of a 12 months exposure group and 20 rats/dose of a 24 months exposure group. Reproductive organs assessed included e.g. adrenals, ovaries, uterus, vagina and mammary gland. Compound-related changes were found in the respiratory tract(LOAEC 0.23 mg/m³), but no treatment related findings on reproductive or any other systemic organ effects were reported.

Applicant's summary and conclusion

Executive summary:

In a further chronic inhalation study with respirable aerosols of 4,4’-MDI, 80 female rats per dose group were whole-body exposed to atmospheres of 0.23, 0.70 or 2.05 mg/m³ for 17 hours/day, 5 days /week for up to 24 months. Full pathological examination was done on 20 rats/dose of a 12 months exposure group and 20 rats/dose of a 24 months exposure group. Reproductive organs assessed included e.g. adrenals, ovaries, uterus, vagina and mammary gland. Again compound-related changes were found in the respiratory tract(LOAEC 0.23 mg/m³), but no treatment related findings on reproductive or any other systemic organ effects were reported (Hoymann et al. 1995; see repeated dose toxicity).