1,1’-Methylenebis(4-isocyanatobenzene) and its reaction products with [(methylethylene)bis(oxy)]dipropanol, butane-1,3-diol and propylene glycol

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: Chronic repeated dose toxicity study

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Study period:

June 1985 - June 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

1994

Materials and methods

Principles of method if other than guideline:

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

GLP compliance:

yes (incl. QA statement)

Test material

Reference

Name:

Unnamed

Type:

Constituent

Type:

Constituent

Details on test material:

SOURCE: polymeric methylene diphenyl diisocyanate (pMDI) was supplied by Bayer AG, Leverkusen.

PURITY: 8 different batches were used, each of which was analyzed by the supplier and fulfilled the following specifications: monomeric MDI 44.8-50.2 % (w/w), NCO-content 31.0-31.7 % (w/w), hydrolysable chlorine 0.06-0.12 % (w/w), total chlorine 0.20-0.37 % (w/w), chlorobenzenes 0.0001-0.0069 % (w/w), phenyl isocyanate 0.003-0.005 % (w/w), sediment content<0.01 % (w/w). Average molecular weight ca. 400, content mol. wt <500 ca. 70%, content mol. wt <1,000 ca. 90 %. An aerosol with 95 % of the particles at < 5 micrometres. The viscosity ranged from 195 to 265 mP.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

See section 7.5.2b Reuzel et al 1990 (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 7.5.2b Reuzel et al 1990 (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 7.5.2b Reuzel et al 1990 (rat, 2y)

Duration of treatment / exposure:

main groups: 2 years; satellite groups: 1 year

Frequency of treatment:

6 hours/day; 5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 0.2, 1.0, 6.0 mg/m3
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 0.19, 0.98, 6.03 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

60 (main groups, 2 years exposure); 10 (satellite groups, 1 year exposure)

Control animals:

yes, sham-exposed

Details on study design:

See section 7.5.2b Reuzel et al 1990 (rat, 2y)

Examinations

Postmortem examinations (parental animals):

At the end of the study rats were killed, autopsied and examined for gross pathological changes.
Organs including testes of all rats of the satellite groups and all survivors of the main groups were weighed. In the satellite groups histopathological examination was carried out of a number of organs and of all gross lesions of all rats of the 2-year study.
Different organs or tissues (including epididymides, mammary glands, ovaries, prostate, seminal vesicles, testes and uterus) and all gross visible lesions were examined by light microscopy of the low and mid-concentration decedents. Moreover, in low and mid-concentration survivors of the main groups, respiratory tissues and all gross lesions were subjected to histopathological examination.

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

In both the satellite and the main groups the absolute and relative organ weights did not show exposure related differences between the control groups and the test groups. However, rats of the low-concentration group showed a statistically higher mean relative testes weight as compared to controls (p<0.05) and mean relative testes weight of the other exposure groups was also higher than controls but not to a

statistically significant degree. The increases were not concentration-related. The ovaries were not weighed.

Gross pathology revealed discoloured, cystic and granular kidneys, enlarged parathyroids, and frequently occurring atrophic testes in male rats of the main study (8/59 in controls; 5/27, 7/25 and 20/60 in the low, mid and high-concentration groups, respectively) associated with nephrosis which was stated as the main cause of death in males. In females of the main groups, tumour masses (17/60, 22/46, 22/43 and 22/58) and secretory activity in mammary glands, ovarian cyst(s) (3/60 in controls, 2/27, 2/18 and 5/59 in exposed groups) and uterine polyps (12/60 in controls; 10/27; 10/18 and 11/59 in low-, mid- and high-concentration groups, respectively) were common findings. Mammary tumours and uterine tumours/polyps were stated as the main cause of death in females. The incidence and distribution of tumours other than lung tumours were not influenced by the substance. The observed lesions in males and females are considered to represent the background pathology of ageing Wistar rats. The significant increase in testis weight in males at the end of the two-year exposure period was not accompanied by histopathological changes. No concentration-effect relationships were present. Therefore, these higher testis weights were considered by the authors to be chance findings unrelated to treatment.

The study authors of the chronic toxicity study identified testes lesions which were observed exclusively in ageing Wistar rats and determined to be common findings or as normal background pathology of ageing Wistar rats. Apparently this conclusion was derived from a comparison with lab-internal historical control data which is unfortunately not available to the registrant. However this statement can be supported by further data:

1. (a)  the absence of a histopathological correlate in the chronic study,

2. (b)  the lesions were only observed in the main group of animals exposed for the entire 24month period (n=60 animals) but not in the satellite group exposed only for 12 months (n=10 animals) (see table),
   (c) the absence of a dose relationship and the lowest test dose being the only dose in which the increase in mean relative testes weights achieved statistical significance (see table).Table: Mean terminal testes to body weight ratio [g/kg bw]

Dose group [mg/m3]	Satellite group (day 366, n=10)	Main group (day 728, n=60)
control	7.13 +/-0.38	6.09 +/-0.14
0.2	6.49 +/-0.3	6.66 +/-0.16*
1	6.99 +/-0.17	6.43 +/-0.14
6	7.02 +/-0.21	6.56 +/-0.15

Anova + Dunnetts tests * p<0.05 ** p<0.01 two sided

(d) the absence of similar lesions in testes assessed in the available subchronic toxicity study in the identical rat strain
(e) in the text book “Diseases of the Wistar rat” (Tucker M.J. 1997, Taylor & Francis, London) it is indicated, that in testes “In 2 year studies the overall incidence of atrophy may reach 80%”.

Applicant's summary and conclusion

Conclusions:

The study authors of the chronic toxicity study identified testes lesions which were observed exclusively in ageing Wistar rats and determined to be common findings or as normal background pathology of ageing Wistar rats.

Executive summary:

Data on macroscopy, gross pathology and histopathology in the reproductive organs of both sexes can furthermore be derived from a 24 months chronic inhalation toxicity and carcinogenicity study of respirable pMDI aerosol in rats. In this study 70 rats/sex/group (each group subdivided into one satellite group of 10 rats/sex and one main group of 60 rats/sex; exposure of the satellite group was limited to 1 year) had been exposed at concentrations of 0, 0.2, 1.0 and 6 mg/m³ for 6h/day, 5 days/week. In the satellite groups histopathological examinations was carried ot of a number of organs and of all gross lesions of all rats of the 2-year study (e.g. including epididymides, mammary glands, ovaries, prostate, seminal vesicles, testes and uterus). Compound-related changes were exclusively found in the respiratory tract (NOAEC 0.2 mg/m³) but no treatment related findings on reproductive or any other systemic organ effects were reported (Reuzel et al. 1994b; see repeated dose toxicity).