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Toxicological information

Repeated dose toxicity: inhalation

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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:
other: NTP standard protocol, cancer bioassay with limited dose range

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- 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

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: vapour
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
2 years
Frequency of treatment:
6 h / day, 5 d / wk
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 500, 1000 ppm for males
Basis:
other: analytically confirmed nominal concentrations
Remarks:
Doses / Concentrations:
0, 250, 500 ppm for females
Basis:
other: analytically confirmed nominal concentrations
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: random (table)
- Dose selection rationale: Based on the results of several preliminary studies up to 90 d duration

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 2/d

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at weighing

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 13 weeks, monthly afterwards

FOOD CONSUMPTION, FOOD EFFICIENCY and WATER CONSUMPTION: no data
HAEMATOLOGY, CLINICAL CHEMISTRY, URINALYSIS, NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY and HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
URT
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
no relevant effect in all investigated tissues

Effect levels

open allclose all
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)
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)
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.

 

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. 

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.

 

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.