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EC number: 905-806-4 | CAS number: -
Mortality incidences in males were comparable in all groups. Female rats showed negatively concentration-related mortality incidences. The number of animals with palpable masses did not differ between test and control animals. No treatment-related differences in body weights were observed between control and test groups.
Hematological examination of rats at day 357-358 revealed no exposure-related differences between the groups. Biochemical examination performed on days 360, 366 and/or 367 was essentially negative. No alterations were observed from parameters measured in urine of rats exposed to polymeric MDI aerosol for 360 days.
Lung weights were statistically significantly increased in both males and females exposed to 6.0 mg/m³ for 12 or 24 months as summarized in the following table 1:
Table 1: Mean absolute lung weights and lung-to-body weight ratios in rats exposed by inhalation to polymeric MDI aerosol for 1 year (satellite groups) or for up to 2 years (main groups)
Polymeric MDI (mg/m3)
Satellite groups (a)
Main groups (b)
2.30 ± 0.15
2.32 ± 0.09
2.44 ± 0.10
2.60 ± 0.06
4.29 ± 0.16
4.48 ± 0.22
4.48 ± 0.16
5.06 ± 0.08**
2.90 ± 0.06
2.88 ± 0.10
2.88 ± 0.08
3.28 ± 0.07**
5.04 ± 0.14
5.00 ± 0.15
5.19 ± 0.24
5.80 ± 0.16**
1.67 ± 0.07
1.66 ± 0.05
1.69 ± 0.06
1.93 ± 0.09*
5.66 ± 0.29
5.63 ± 0.15
5.61 ± 0.21
6.51 ± 0.22*
2.10 ± 0.06
2.09 ± 0.04
2.06 ± 0.04
2.41 ± 0.05**
6.14 ± 0.28
5.87 ± 0.09
5.68 ± 0.11
6.68 ± 0.17
(a) Number of lungs weighed/sex/group was 10 (b) Number of lungs weighed/sex/group varied from 35 to 50
* p<0.05; ** p<0.01
No treatment-related gross changes were found in animals exposed for 12 months. Gross examination of animals exposed for 24 months revealed increased incidence of lungs with spotted surface and/or discoloured appearance in male rats exposed to 6.0 mg/m3.
Histopathology (main groups exposed over 2 years):
Nose: increased incidence of rats with a higher degree of basal cell hyperplasia frequently accompanied by hyperplasia of Bowman's glands in the olfactory epithelium in the nose at levels of 1.0 and 6.0 mg/m³. At 6.0 mg/m³ basal cell hyperplasia occurred in 32/60 males and 49/60 females against 14/60 and 4/60 for the corresponding controls.
Lungs: incidences of non-neoplastic findings and tumors are summarized in the following table 2:
Table 2: Number of rats with non-neoplastic findings and tumors in lungs after 2-year exposure to polymeric MDI (main groups)
- Macrophages with yellow pigment
- Localized fibrosis
- Alveolar duct epithelialization
- Localized alveolar bronchiolization
- Mineralized deposits in the bronchial and alveolar region
Mediastinal lymph nodes: increased incidence of rats with an accumulation of macrophages with yellow pigment at levels of 1.0 and 6.0 mg/m³. At 6.0 mg/m³ this finding occurred in 50/60 males and 43/60 females against 0/60 for the corresponding controls.
Other organs: the incidence and distribution of other tumour types was not affected by treatment.
Histopathology (satellite groups exposed over 1 year):
Rats killed after 1 year of exposure had treatment-related histopathological changes in the nasal cavity, lungs, and mediastinal lymph nodes starting at 1.0 mg/m3, but to a lower degree of severity compared to animals exposed over 2 years. There was no microscopic evidence of lung tumors or any other tumors following exposure to polymeric MDI for 1 year.
In a combined chronic toxicity and carcinogenicity study rats were exposed for 6 hours/day, 5 days/week for 1 (satellite groups) or 2 years (main groups) to polymeric MDI aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg/m3. The effect of chronic exposure of rats to respirable polymeric MDI aerosol was confined to the respiratory tract. The compound-related changes were found in the nasal cavity, the lungs and the mediastinal lymph nodes, and to some degree they were already present after 1 year of exposure. Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m³ over 2 years was related to the occurence of pulmonary tumors in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas).
In this 2-year rat study the NOAEC was 0.2 mg/m3 for the repeated dose toxicity of polymeric MDI. The LOAEC was set on 1.0 mg/m3.
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