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EC number: 202-597-5
CAS number: 97-63-2
1. Original study
(Reno FE, 1979):
The mean analytical
concentration was evaluated. The overall mean concentrations of MMA
vapour were 25.0, 99.8 and 396.1 ppm for the 25, 100 and 400 ppm
exposure groups, respectively.
rates were relatively low through week 78. High mortality was observed
through week 104. The author indicates that the increase in mortality
was probably due to aging, not related to test substance exposure. The
mortality rates for treated groups were comparable to the control group.
A summary of the mortality rates (%) is provided below.
Dose group (ppm)
Negative Control (0)
No signs of test
substance-related toxicity were observed in any of the treated animals
throughout the 104-week exposure period. The most frequent observations
included cloudy eye(s) and bloody crust around one or both eyes. The
author reported that these findings occurred with approximately the same
frequencies in treated and control groups.
Male body weights were
significantly higher in the mid-level exposure group at week 24, lower
weights in the low-level exposure group at week 104, and lower weights
of the high-level exposure group at weeks 28 and 78. In the females, the
low-level exposure groups showed a significant decrease in body weight
at weeks 60, 72 and 78 and an increase at weeks 12 and 24. The females
in the mid-level exposure group showed a significant decrease at weeks
52, 60 and 78 and in the high-level exposure group at weeks 28, 36, 52,
60, 72, 78 and 90. The author concluded, the body weight reduction
observed in the females exposed to ca. 1.64 mg/L (400 ppm) MMA was test
observations were noted at weeks 13, 52 and 102. The author reports that
no consistent ocular abnormalities were noted at weeks 13 and 52. Ocular
findings noted at week 102 included cataracts, pale coloration, corneal
cloudiness and red discharge. The cataract findings were considered to
be caused by aging.
Evaluation of the
haematology and clinical chemistry data did not reveal any remarkable
trends. Statistical analyses showed numerous significant differences
between the treated and the control groups; however, these differences
were considered sporadic and were considered by the author a reflection
of sampling and biological variability. A transitory appearance of
occult blood was observed in all groups at week 52. All remaining
intervals were generally unremarkable.
significant increase in absolute and relative organ weights of the
females exposed to ca. 1.64 mg/L (400 ppm) MMA was observed in the
lungs, liver, kidneys, and ovaries at week 13. A statistically
significant decrease in absolute and relative thyroid and adrenal
weights were observed in both males and females in the high-level
exposure group at week 52. Absolute thyroid and adrenal weights were
significantly higher in the males exposed to ca. 0.41 mg/L (100 ppm),
MMA for 52 weeks. Other significant differences were noted at weeks 52
and 104; however, the author concluded that no consistent dose-related
pattern was established.
Findings noted in
animals that were sacrificed at weeks 13 and 52 were mainly
discolorations of the lung and liver. None of the findings were
considered treatment-related. Tissue mass findings for animals
sacrificed at week 104 were typical for the age and the species of rats.
No treatment-related differences with respect to the frequency were
histopathological findings were noted in the rats exposed to ca. 1.64
mg/L (400 ppm) MMA for 13 weeks. Findings were consistent among groups
and were typical for rats of this age and strain.
histopathological findings were limited to a very slight increase in the
lesions of mild rhinitis observed in the mucosal lining of the nasal
turbinates. A summary of the lesions is provided below.
Incidence of Lesions
in Nasal Mucosa
No. of Nasal Turbinates Examined
Distended Submucosal Glands
Squamous Metaplasia (focal)
*Groups 1, 2, 3 and 4
were exposed to ca. 0, 0.10, 0.41 and 1.64 mg/L (0, 25, 100 and 400 ppm)
treatment-related effect could be established. Although lesions of mild
rhinitis occurred more often in treated rats than control rats, it could
not be determined if the rhinitis was a result of direct chemical insult
to the turbinate area or whether the presence of MMA vapors predisposed
the rats to an increase in spontaneous disease. [NOTE - Subsequent
evaluation of the nasal lesions (Lomax et al., 1997) indicated that
there were exposure related nasal lesions at ca. 0.10 and 0.41 mg/L (100
and 400 ppm)]. Neoplasms and spontaneous disease lesions were observed
with comparable frequency in control and treated rats. Chronic nephritis
was observed in most rats; however, it was more pronounced in males.
2. Re-Evaluation of
the study (Lomax LG et al. (1997)):
The mean analytical
concentrations of the test substance in the exposure chambers were 25.0,
99.8 and 396.1 ppm less than 10% per dose level.
Mortality rates for
the treated animals were similar to those of the controls. No signs of
treatment-related toxicity were observed. At the 13, 52 and 104-week
observation intervals, cloudy eyes and bloody crusts around one or both
eyes were noted in all of the treatment groups, as well as the control
animals. Body weights for males were lower than the control at various
intervals but overall were considered equivalent over the 104-week
period. Mean body weights for females were lower than the controls at
ca. 1.64 mg/L (400 ppm) after week 52. Haematology, clinical chemistry
and urinalyses did not indicate any treatment-related effects in any of
the parameters evaluated.
Gross necropsy of the
rats sacrificed at weeks 13 and 52 did not show any treatment-related
information was obtained from the reevaluation of the nasal tissues from
this study originally conducted by Reno et al.(1979) - see also summary
for this study in this Dossier. Microscopic evaluation of the nasal
cavity sections obtained from the animals exposed to the test substance
for 13 weeks showed degeneration of the neuroepithelial cell lining of
the dorsal meatus in conjunction with atrophy of Bowman's glands and
focal basal cell hyperplasia. Lesions were identified on the tips of the
maxilloturbinates and nasoturbinates and focally along the nasal septum
in the more anterior regions of the nose. These lesions were
chronic active inflammation, respiratory epithelial hyperplasia and
squamous metaplasia. No microscopic findings were identified in the
ocular tissue or the lungs or other tissues. Blocks of the nasal
cavities of animals from the 52-week sacrifice were unable to be located
and, therefore, were not evaluated. No new findings were identified in
the tissues that were available for animals exposed to the test
substance for 52 weeks. Spontaneous disease lesions included early
respiratory disease in both the control animals and the animals exposed
to 400 ppm of the test substance. Also focal areas of pneumonitis were
observed in two females in the control group.
Gross necropsy after
two years of exposure to the test substance showed no treatment-related
effects. The nasal cavity was the target organ for chronic toxicity.
Rats exposed to the 100 and 400 ppm dose group had dose-dependent
lesions in the anterior portions of the nasal cavity. The olfactory
epithelium lining the dorsal meatus in the anterior region of the nasal
cavity was affected by exposure to higher concentrations of the test
substance. The microscopic changes consisted of degeneration of the
olfactory epithelium and underlying Bowman's glands, hyperplasia of
basal cells, replacement of olfactory epithelium by ciliated epithelium
and inflammation of
the mucosa and/or
submucosa. Lesions tended to be bilateral in distribution. The olfactory
lesions in rats exposed to 100 ppm were localized in the more posterior
(level 3) portion of the dorsal meatus, while those in animals exposed
to ca. 1.64 mg/L (400 ppm) were found in levels 2 and 3. Hyperplasia of
glands in the lamina propria and/or goblet cells and inflammation of the
mucosa/lamina propria were observed in the respiratory epithelium in the
high exposure group animals. No effects were seen in nasal epithelium of
rats exposed to ca. 0.10 mg/L (25 ppm) MMA. No statistically significant
differences were observed in the frequency of tumours between the rats
exposed to ca. 1.64 mg/L (400 ppm) of the test substance and that of the
controls. In female rats exposed to ca. 1.64 mg/L (400 ppm) of the test
substance, a statistically significant decrease in pituitary
adenoma/carcinomas and mammary gland fibroadenomas was recorded. In male
rats, a decreased incidence of pheochromocytoma was observed.
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