Methyl methacrylate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Cross-reference

Reason / purpose for cross-reference:

read-across source

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Methyl methacrylate

EC Number:

201-297-1

EC Name:

Methyl methacrylate

Cas Number:

80-62-6

Molecular formula:

C5H8O2

IUPAC Name:

methyl 2-methylprop-2-enoate

Test material form:

liquid

Specific details on test material used for the study:

- Name of test material (as cited in study report): methyl methacrylate
- Molecular weight (if other than submission substance): 100.1
- Smiles notation (if other than submission substance):
- Physical state: liquid
- Analytical purity: > 99.8 %
- Purity test date: several times throughout the test
- Stability under test conditions: stable
- Other: stabilised commercila grad material

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

mortality observed, non-treatment-related

Description (incidence):

No significant differences in survival were observed between any groups of either sex.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of 1000-ppm male rats were 5%-10% lower than those of the controls after week 81. Mean body weights of 500-ppm female rats were 6%-11%l ower than those of the controls after week 73.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

A statistically significant positive trend in the incidence of mononuclear cell leukemia occurred in female rats exposed to 500-ppm (incidence of 22%, 26% and 40% for the control, 250 ppm and 500 ppm groups, respectively). However, life table analysis, which can be regarded as more appropriate for life-threatening lesions, showed no difference. The incidence of mononuclear cell leukemia in the three groups of male rats was not statistically different by life table analysis.

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Nasal Cavity and Olfactory Sensory Epithelium:
Serious and suppurative inflammation and degeneration of the olfactory epithelium in the nasal cavity were observed at increased incidences in exposed male and female rats relative to controls. Serous inflammation was characterized by noncellular mucus in the lumen of the posterior region of the nasal cavity.
Suppurative inflammation was characterized by an infiltration of neutrophils and varying numbers of mononuclear cells into the mucosa and submucosa of the nasal turbinates and wall of the nasal cavity. Degeneration of the olfactory epithelium was characterized by a loss of sensory neuroepithelial cells from the epithelium (atrophy) and, in the most severely affected areas, replacement by respiratory epithelium (metaplasia). This degeneration was accompanied by variable atrophy of the nerve bundles in the submucosa.

Lung: Alveolar macrophages were observed at increased incidences in exposed male and female rats. The severity in all groups was considered minimal. Focal or multifocal fibrosis was observed at an increased incidence in 500- ppm female rats.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Pituitary Gland: Pituitary gland adenomas or carcinomas (combined) in male rats occurred with a significant negative trend, and the incidence in the 1,000 ppm group was significantly lower than that in the controls . The
incidences of pituitary gland adenomas in the three groups of female rats were not different statistically.
Preputial Gland: Preputial gland adenomas and carcinomas occurred in male rats with a significant negative trend, and the incidence in the high dose group was significantly lower than that in the controls .

Hematopoietic System: Mononuclear cell leukemia in female rats occurred with a significant positive trend, and the incidence in the 500-ppm group was significantly greater than that in the controls by the incidental tumor test but not by life table analysis. The latter test procedure is generally considered more appropriate for life-threatening lesions. The incidences of mononuclear cell leukemia in the three groups of male rats were not statistically different by life table analysis.

The mononuclear cell leukemia in female rats in the control and dosed groups was classified according to the extent of involvement of the spleen and its advancement to other organs. The following criteria were used:
Stage 1. Spleen not enlarged or only slightly enlarged with small numbers of neoplastic mononuclear cells in the red pulp; no or very few mononuclear cells in the liver sinusoids. No identifiable neoplastic cells in other organs.
Stage 2. Spleen moderately enlarged with moderate to large numbers of mononuclear cells in the red pulp; architectural features including lymphoid follicles and periarteriolar lymphocytic sheaths remain intact. Minimal to moderate involvement of the liver. Mononuclear cells may be evident in blood vessels in other organs, but aggregates/masses of neoplastic cells generally limited to spleen and liver.

Stage 3. Advance disease with multiple organ involvement. Spleen usually markedly enlarged with effacement of normal architectural features by accumulated neoplastic cells. Liver moderately to markedly enlarged and nodular; hepatic parenchyma shows variable degenerative changes associated with the accumulation of neoplastic cells. Accumulations of neoplastic mononuclear cells in other organs including
lung, lymph nodes, kidney, brain, and adrenal gland.

According to these criteria, there were no differences in the character of the mononuclear cell leukemia found in the dosed female rats and the controls.

Effect levels

1

Dose descriptor:

LOAEC

Remarks:

for local effects in the URT (no NOAEC identified)

Effect level:

250 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Histopathology (Irritation)

2

Key result

Dose descriptor:

NOAEC

Remarks:

for systemic effects

Effect level:

500 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Gross pathology, Histopathology (organ effects)

3

Dose descriptor:

NOAEC

Effect level:

1 000 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Gross pathology, Histopathology (organs)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Mortality: No difference in survival between treated and untreated groups.

Histopathology:

Site / Lesion Males	Control [0 ppm]	Low. Conc. [500 ppm]	High Conc. [1000 ppm]
Nasal Cavity /            Serous inflammation            Suppurative inflammation	0/50 11/50	37/50 21/50	44/50 30/50
Olfactory sensory epithelium /            Degeneration	7/50	39/50	42/50
Lung /            Alveolar macrophages            Focal or multifocal fibrosis	6/49  6/49	20/49  6/49	16/50  5/50
Site / Lesion Females	Control [0 ppm]	Low. Conc. [250 ppm]	High Conc. [500 ppm]
Nasal Cavity /            Serous inflammation            Suppurative inflammation	4/50 7/50	17/50 12/50	32/50 12/50
Olfactory sensory epithelium /            Degeneration	2/50	39/50	44/50
Lung /            Alveolar macrophages            Focal or multifocal fibrosis	9/50 1/50	14/50  2/50	16/50  7/50

 

No histopathological findings other than local findings in the respiratory tract. Systemic histopathological effects, as for example in the brain in females particularly at 2000 ppm and above in the subchronic range finding study (Batelle, 1980), are absent in this 104 week study.

Body weight: Mean body weight gain was reduced in females at 500 ppm resulting in 6 -11% lower body weights after week 73 and in males at 1000 ppm which were 5 -10 % lower than controls after week 81.

There was no treatment-related increase in tumour incidence.

Applicant's summary and conclusion

Conclusions:

The primary finding in this study was inflammation of rat nasal cavity as well as olfactory epithelial degeneration at all exposure levels in male and female rats. For local effects the LOAEC was 250 ppm in this study while a NOAEC could not be found. 
In contrast to the 90 d range finding study with histopathological changes in females at exposures of 1000 ppm and above (Battelle, 1980), no other significant histopathological changes were reported in male and female rats after 104-week exposures to MMA vapour in this study. Based on this a NOEC for systemic effects of 500 ppm is derived.

Executive summary:

In this104-week study with groups of 50 animals each, male rats were treated with MMA vapour by whole-body exposure to 500 or 1000 ppm while female rats were exposed to 250 or 500 ppm. Control animals were only treated with air.

The primary finding was inflammation of rat nasal cavity as well as olfactory epithelial degeneration at all exposure levels in male and female rats. For local effects the LOAEC was 250 ppm in this study while a NOAEC could not be found. 

No other significant histopathological changes were reported in male and female rats after 104-week exposures to MMA vapour in this study. Based on this a NOEC for systemic effects of 500 ppm is derived.

Male and female rat body weights were lower at the 1000 ppm (5-10%) and 500 ppm (6-11%) exposure levels, respectively, presumably due to reduced food consumption due to nasal irritation and damage of olfactory epithelium. While food consumption was not recorded in this study this association is confirmed by two other studies, the developmental toxicity study with MMA with reduced food consumption and reduced body weight gain at concentrations higher than 99 ppm (Solomon, 1993) and a subchronic inhalation study with methacrylic acid where there was also an association of irritative effects in the nose and reduced food consumption and reduced body weight gain (BASF, 2008). Consequently, reduced body weight gain, while clearly treatment-related - is considered to be secondary to the local effects in the nose and not the result of true systemic toxicity.