Methacrylic anhydride

Carcinogenicity

Description of key information

No data available for MAAH.

Read across data from methyl methacrylate, MMA (metabolite donor substance for methacrylic acid, MAA, as primary metabolite and hydrolysis product; read across justification see attached document):

Chronic inhal, NTP protocol, rat: negative

Chronic inhal, NTP protocol, mouse: negative

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Method and results sufficient described, similar to OECD-guideline 451, NTP-study.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

- Principle of test: 2 year study, inhalation
- Short description of test conditions: groups of 50 males were exposed for 5 days per week, target conc. of 0, 500 and 1000 ppm, groups of 50 females were exposed for 5 days per week, target conc. 0, 250 and 500 ppm,
- Parameters analyzed/observed: survival, body weight, clinical signs, hematopoietic system, pituitary gland, prepuital gland, nasal cavity and olfactory sensory epithelium, lung

GLP compliance:

not specified

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 6-5486; 377109
- Expiration date of the lot/batch 28.01.1981
- Purity test date: > 99 %
- water content: < 0.1 %
- Supplier: Rohm&Hass, Co (Philadelphia)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in steel drums at room temperature
- Stability test:periodically analyzed by IR-spectroscopy and gas chromatograpy during the test period, stabel for 2 weeks at 60 °C
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

Species:

rat

Strain:

Fischer 344

Details on species / strain selection:

- Source: Charles River Breeding Laboratories

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Age at study initiation: 7-8 weeks
- Weight at study initiation: males 151-155g; females 117-119g (mean weights per treatment group)
- Housing: individually in stainless steel cages within the exposure chambers
- Acclimation period: 3 weeks
- Feed and water: both freely avaiable except during exposre period, when only water wa available

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

All animals were exposed to MMA vapors via whole body inhalation. MMA was vaporized at 50 ºC diluted with air and introduced into the chambers.  GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Methyl methacrylate was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable drift-free pump rates. The vaporizer was heated to 50° ± 2° C, and the study material vapor, along with an air stream, entered the test chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Methyl methacrylate concentrations were monitored on-line twice during each exposure hour, initially by a photoionization detector and later by gas chromatographic analysis

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Uniformity of the vapor concentration in the chambers was measured periodically throughout the studies. The mean concentrations in the chambers over the two-year study were 249 ± 1, 499 ± 17 and 984 ± 36 ppm for the 250, 500 and 1000 ppm exposure groups, respectively.

Duration of treatment / exposure:

2 years (102 weeks)

Frequency of treatment:

6 hours/day, 5 days/week

Post exposure period:

no

Dose / conc.:

1.03 mg/L air (nominal)

Remarks:

females, corresponding to 250 ppm

Dose / conc.:

2.05 mg/L air (nominal)

Remarks:

males and females, corresponding to 500 ppm

Dose / conc.:

4.1 mg/L air (nominal)

Remarks:

males, corresponding to 1000 ppm

No. of animals per sex per dose:

50

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: based on the results of the subchronic study

Positive control:

no

Observations and examinations performed and frequency:

Observations: Animals were observed twice daily for mortality and morbidity. Body weights were measured prior to study initiation, weekly for the first 13 weeks and monthly thereafter. A more detailed clinical observation was performed on each animal at the time of body weight measurement.

Sacrifice and pathology:

Necropsy: All animals were subjected to a gross necropsy, unless they were excessively autolyzed or cannibalized, missexed, or found missing.
A histological evaluation was performed with the following tissues: gross  lesions and tissue masses, regional lymph nodes, mandibular lymph nodes, sternebrae including marrow, thyroid glands, parathyroids, small  intestine, rectum, colon, liver, mammary gland, prostate, testes,  epididymis, or ovaries/uterus, lungs and mainstem bronchi, nasal cavity  and turbinates, skin , heart, esophagus, stomach, salivary gland, brain,  thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary  bladder, pituitary gland, preputial or clitoral gland and tracheobronchial lymph nodes.  

Statistics:

Data analysis: Survival probability was estimated using the product limit procedure of Kaplan and Meier (1958). Statistical analysis of survival was completed according to Cox (1972) and to Tarone's life table test (1975). P values for the survival analysis were two-sided and the analysis of the tumor incidence  was evaluated using Mantel and Haenszel (1959). In addition the Fisher Exact Test for pairwise comparisons and the Cochran-Armitage linear trend test was conducted.

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No significant differences were observed for mortality in any of the exposure groups when compared to that of the controls.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Mean body weights of the males in the 1000-ppm group were 5 - 10% reduced from that of the control group after week 81 and the mean body weights of the females in the 500-ppm group decreased by 6 - 11% from that 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 specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Pituitary and preputial gland adenomas were significantly reduced in the male rats exposed to 1000 ppm test substance.
Serious and suppurative inflammation and degeneration of the olfactory epithelium in the nasal cavity was observed at an increased incidence in the treated rats when compared to the controls. Although alveolar macrophages were observed at an increased incidence treated rats, the severity was considered minimal. An increased incidence of focal or multifocal fibrosis was observed females exposed to 500 ppm of the test substance.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related tumors were observed.

Relevance of carcinogenic effects / potential:

no

Dose descriptor:

NOAEC

Effect level:

>= 2.05 mg/L air (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects observed; corresponding to 500 ppm

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEC

Effect level:

>= 4.1 mg/L air (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no effects observed; corresponding to 1000 ppm

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEC

Effect level:

>= 2.05 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

other: no biologically relevant adverse systemic effects observed; corresponding to 500 ppm

Remarks on result:

other:

Remarks:

Effect type: other: systemic toxicity (migrated information)

Dose descriptor:

LOAEC

Effect level:

ca. 1.03 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

other: Inflammation and degeneration of the olfactory epithelium in the nasal cavity; corresponding to 250 ppm

Remarks on result:

other:

Remarks:

Effect type: other: local toxicity (migrated information)

Effects on body weight gain

Reduced body weights of the high dosed animals by maximum 11% are considered as secondary effects following the inflammatory effects in the URT and therefore not relevant for the assessment of a systemic NOAEC.

Hematological effects

Mononuclear cell leukemia has a high spontaneous incidence in Fischer 344 rats. Based on the lack of statistical significance and the normal occurrence of this 

neoplasm, the increased incidence was not considered biologically significant. In support of this conclusion, a classification of the leukemia into three 

stages of severity showed that there were no differences in the characteristics of the leukemia between the exposed and control females, and, further, there 

was no increase in this neoplasm in males exposed to 1000 ppm MMA.

Conclusions:

In a two years inhalation toxicology and carcinogenesis study (NTP) in F344 rats methyl methacrylate did not induce neoplasms in the highest doses testd (500 ppm /females, 1000 ppm/males)

Executive summary:

In a two years inhalation toxicology and carcinogenesis study (NTP) in F344 rats with methyl methacrylate50 males and 50 females of each species male rats were exposed to 0, 500, or 1,000 ppm methyl methacrylate by inhalation and female rats were exposed to -0, 250, or 500 ppm methyl methacrylate by inhalation.

Animals were exposed 6 hld, 5 d/wk for 102 wk. Animals were observed twice per day, weighed once per week for the first 13 wk and monthly thereafter; individual clinical examinations were made at weighing.

 

Necropsy and histologic examination performed on all animals . The following tissues were examined: gross lesions and tissue masses, regional lymph nodes, mandibular lymph node, sternebrae including marrow, thyroid gland, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate/testes/epididymis or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin, heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland, and tracheobronchial lymph nodes

 

In this study methyl methacrylate did not induce neoplasms in rats in the highest doses tested (500 ppm /females, 1000 ppm/males).

 

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Method and results sufficient described, similar to OECD-guideline 451, NTP-study.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

- Principle of test: 2 year study, inhalation
- Short description of test conditions: groups of 50 mice of each sex were exposed for 5 days per week, target conc. of 0, 500 and 1000 ppm
- Parameters analyzed/observed: survival, body weight, clinical signs, pituitary gland, prepuital gland, nasal cavity and olfactory sensory epithelium, lung, uterus, liver.

GLP compliance:

not specified

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 6-5486; 377109
- Expiration date of the lot/batch 28.01.1981
- Purity test date: > 99 %
- water content: < 0.1 %
- Supplier: Rohm&Hass, Co (Philadelphia)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in steel drums at room temperature
- Stability test:periodically analyzed by IR-spectroscopy and gas chromatograpy during the test period, stabel for 2 weeks at 60 °C
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males 21.8-23.8 g; females 16.6-20.0 (mean weights per treatment group)
- Housing: individually in stainless steel cages within the exposure chambers
- Acclimation period: 3 weeks
- Feed and water: both freely avaiable except during exposre period, when only water wa available

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

All animals were exposed to MMA vapors via whole body inhalation. MMA was vaporized at 50 ºC diluted with air and introduced into the chambers.  GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Methyl methacrylate was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable drift-free pump rates. The vaporizer was heated to 50° ± 2° C, and the study material vapor, along with an air stream, entered the test chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Methyl methacrylate concentrations were monitored on-line twice during each exposure hour, initially by a photoionization detector and later by gas chromatographic analysis

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Uniformity of the vapor concentration in the chambers was measured periodically throughout the studies. The mean concentrations in the chambers over the two-year study were 499 ± 17 and 984 ± 36 for the 500 and 1000 ppm exposure groups, respectively.

Duration of treatment / exposure:

2 years (102 weeks)

Frequency of treatment:

6 hours per day, 5 days per week

Post exposure period:

no

Dose / conc.:

2.05 mg/L air (nominal)

Remarks:

male/female(corresponding to 500ppm

Dose / conc.:

4.1 mg/L air (nominal)

Remarks:

male/female(corresponding to 1000ppm

No. of animals per sex per dose:

50

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: Based on the results of the subchronic study

Positive control:

no

Observations and examinations performed and frequency:

Observations: Animals were observed twice daily for mortality and morbidity. Body weights were measured prior to study initiation, weekly or the first 13 weeks and monthly thereafter. A more detailed clinical observation was performed on each animal at the time of body weight measurement.

Sacrifice and pathology:

Necropsy: All animals were subjected to a gross necropsy, unless they were excessively autolyzed or cannibalized, missexed, or found missing.
A histological evaluation was performed with the following tissues: gross lesions and tissue masses, regional lymph nodes, mandibular lymph nodes, sternebrae including marrow, thyroid glands, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate, testes, epididymis, or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin , heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland and tracheobronchial lymph nodes.

Statistics:

Data analysis: Survival probability was estimated using the product limit procedure of Kaplan and Meier (1958). Statistical analysis of survival was completed according to Cox (1972) and to Tarone's life table test (1975). P values for the survival analysis were two-sided and the analysis of the tumor incidence was evaluated using Mantel and Haenszel (1959). In addition the Fisher Exact Test for pairwise comparisons and the Cochran-Armitage linear trend test were conducted.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No significant differences were observed in mortality for any of the exposure groups when compared to that of the controls.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of both male and female mice at both concentrations were lower than those of the controls throughout most of the study (males: up to 16% lower mean body weight; females: up to 17%).

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:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Acute and chronic inflammation, epithelial hyperplasia, cytoplasmic inclusions in the epithelial cells, and degeneration of the olfactory epithelium in the nasal cavity occurred at increased incidences in male and female mice exposed to the test substance. Accumulation of homogeneous, eosinophilic material in the cytoplasm of cells, primarily of the respiratory epithelium (cytoplasmic inclusions) was significantly increased in treated animals when compared to that of the controls.
Uterine adenocarcinomas were reduced in animals from both of the treatment groups, but statistical significance was not observed.
In the lungs, interstitial inflammation was increased in the male mice from the high-group, while alveolar/bronchiolar adenomas and alveolar/bronchiolar adenomas and carcinomas (combined) were significantly reduced in the male mice exposed to 500 and 1000 ppm. Pituitary gland adenomas and adenomas and adenocarcinomas (combined) were significantly reduced in the female mice in each of the treatment groups. Hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were significantly reduced in males and female mice exposed to the test substance relative to the controls.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related tumors were observed

Dose descriptor:

NOAEC

Effect level:

>= 4.1 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed; corresponding to 1000 ppm

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEC

Effect level:

>= 4.1 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no biologically relevant adverse systemic effects observed; corresponding to 1000 ppm

Remarks on result:

other:

Remarks:

Effect type: other: systemic toxicity (migrated information)

Dose descriptor:

LOAEC

Effect level:

ca. 2.05 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: inflammation, epithelial hyperplasia, cytoplasmic inclusions in the epithelial cells, and degeneration of the olfactory epithelium in the nasal cavity; corresponding to 500 ppm

Remarks on result:

other:

Remarks:

Effect type: other: local toxicity (migrated information)

Effects on body weight gain

Reduced body weights of the high dosed animals by maximum 17% are considered as secondary effects following the inflammatory effects in the URT and therefore not relevant for the assessment of a systemic NOAEC.

Conclusions:

In a two years inhalation toxicology and carcinogenesis study (NTP) in B6CF31 mice methyl methacrylate did not induce neoplasms in the highest doses testd (1000 ppm/males and females)

Executive summary:

In a two years inhalation toxicology and carcinogenesis study (NTP) in B6CF31 mice with methyl methacrylate50 males and 50 females of each species male and female mice were exposed to 0, 500, or 1,000 ppm methyl methacrylate by inhalation.

 

Animals were exposed 6 hld, 5 d/wk for 102 wk. Animals were observed twice per day, weighed once per week for the first 13 wk and monthly thereafter; individual clinical examinations were made at weighing.

 

Necropsy and histologic examination performed on all animals . The following tissues were examined: gross lesions and tissue masses, regional lymph nodes, mandibular lymph node, sternebrae including marrow, thyroid gland, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate/testes/epididymis or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin, heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland, and tracheobronchial lymph nodes

 

In this study methyl methacrylate did not induce neoplasms in mice in the highest doses tested (1000 ppm, males and females)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

In absence of treatment-related tumors in rats and mice and gentoxicity in vivo found in MMA, the metabolite donor substance of MAAH, there is no indication for a classification of MAAH according to CLP (1272/2008/ EC) and UN-GHS.

Additional information

There are no studies available for carcinogenicity of methacrylic anhydride. As methacrylic anhydride was demonstrated to hydrolyse very fast into methacrylic acid, and methacrylic acid is the hydrolysis product and primary metabolite of methacrylic anhydride, this endpoint is covered by read across to data of methyl methacrylate (MMA), the metabolite donor substance of MAA (see attached read across justification).

EU ESR on MMA concluded: “The combined chronic toxicity and carcinogenicity study on methyl methacrylate of Rohm and Haas (1979a, re-evaluated by Lomax, 1992) reported in Section 4.1.2.6 did not reveal any significant incidence of tumours or increase of tumour incidence. One male each out of a total of 49, respectively 47 males exposed to 100 and 400 ppm methyl methacrylate had a small solitary polypoid mass attached to the lateral wall of one side of the anterior nasal cavity. Both masses were composed of well differentiated pseudoglandular structures arising from respiratory epithelium diagnosed as adenomas. Both animals had chronic inflammation of the respiratory epithelial region. An association of the nasal adenomas to methyl methacrylate inhalation were considered to be unlikely, because the incidence was not significantly increased in comparison to controls without any nasaltumour and the findings were not confirmed by other studies. However, historical data show that adenomas from respiratory epithelium are very rare tumours in rats with a spontaneous rate of 0-0.1 % for F344 male and female rats (Haseman et al., 1990).

 

Groups of 50 male F344/N rats were exposed to methyl methacrylate (purity > 99 %; containing 0.04 mg/l equivalent to 10 ppm monomethylethyl ether of hydroquinone as an inhibitor of polymerization) by inhalation at 0, 2.1, 4.2 mg/l (equivalent to 500 or 1000 ppm), female F344/N rats at 0, 1.0 or 2.1 mg/l (equivalent to 250 or 500 ppm) and male and female B6C3F1 mice at 2.1 or 4.2 mg/l (equivalent to 500 or 1000 ppm), 6 hours a day, 5 days a week for 102 weeks (NTP, 1986; Chan et al., 1988). Animals were killed at 111-112 weeks (rats) or 113-114 weeks (mice) of age. No significant differences of the survival rates were observed between any groups of rats and mice. During most of the second year of the study, the mean body weights of treated male mice and high-dose female mice were 10-18 % lower than those of the controls. The marginal increase in the incidence of mononuclear-cell leukaemia observed in female rats (control 11/50; low-dose 13/50; high-dose 20/50) fell within the range of values seen in historical controls. Both in mice and rats no treatment-related tumours were observed.”

No treatment-related increases in tumour incidence occurred in Golden hamsters with groups of 53-56 males and 56-59 females exposed to 0, 25, 100 or 400 ppm (0, 102.5, 410 or 1640 mg/m³) MMA 6 h/d, 5 d/wk for 78 weeks (no interim sacrifice). At the high-dose, body weight decreased and mortality increased in high dose males (Rohm and Haas, 1979c, cited from Chan et al. 1994; Lomax et al., 1997). After week 60, males exposed to 400 ppm and to 25 ppm had significantly lower body weight during some weeks. There were no clinical signs or haematological effects attributable to exposure to methyl methacrylate at either the 52- or 78- week sampling times. No gross haematological changes indicative for a possible exposure-related effect were observed.”