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Toxicological information

Carcinogenicity

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Description of key information

No data available for EMA.

Data in animals and in humans are available for the methacrylic metabolite donor substance MMA and this has been reviewed in the EU ESR on this substance. However, it can be concluded that all members of the category are not mutagenic or genotoxic, hence, further testing is not necessary.

Beside inadquate animal data (as carried out in too high doses for the purpose of risk evaluation of alcoholic beverages) there is evidence from epidemiological studies (again assessing the impact of alcoholic beverage consumption) that no such hazard exists from potential exposure to ethanol in the work place or from the use of ethanol in consumer products, as stated by OECD SIDS (2004).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
With regard to carcinogenicity testing, the number of animals used in this test is below current guideline requirements. The power of this study and the negative finding have to be placed into perspective with the other three negative in vivo studies, the absence of genotoxicity and the lack of positive evidence in the cancer mortality studies on MMA.
Qualifier:
no guideline followed
GLP compliance:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: drinking water
Duration of treatment / exposure:
104 weeks (2 years)
Frequency of treatment:
Daily, ad libitum
Post exposure period:
no
Remarks:
Doses / Concentrations:
6, 60 and 2000 ppm at the start of the study; raised after 5 months to 7, 70 and 2000 ppm
Basis:
nominal in water
Remarks:
Doses / Concentrations:
ca. 12, 120, 3300 ppm (corresponding to roughly 0.6, 6 and 165 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J., 2000)
Basis:
other: on the basis of fluid and food consumption observations
No. of animals per sex per dose:
25
Control animals:
other: yes, concurrent negative control group
Details on study design:
Animals: Twenty-five male and female albino (Wistar) rats were administered 6, 60 or 2000 ppm of methyl methacrylate in the drinking water. The concentrations of the low- and mid-dose groups were increased to 7 and 70 ppm at the beginning of the fifth month of the study. The animals were individually housed and provided food ad libitum.  
Observations and examinations performed and frequency:
Body weights were measured prior to study initiation, at weeks 1, 3, 6, 13, 26, 52, 78 and 104. Food and water consumption was measured over a three day period at the end of one and four weeks, monthly through month six and during even months thereafter. Hematological measurements, including hematocrit, hemoglobin, total white and differential white cell counts, were obtained from five rats from each sex in each treatment level at three month intervals. Pooled urine samples were collected from five rats per sex from each treatment group every three months to evaluate urinary concentrations of reducing substances and proteins.
Sacrifice and pathology:
Necropsy: At sacrifice, organ to bodyweight ratios were made for the heart, spleen, kidney, liver and testes. Select tissues collected and preserved from all survivors and decedents included: heart, lung, liver, kidney, urinary bladder, spleen, gastroenteric, skeletal muscle, bone marrow, skin, brain, thyroid, adrenal, pancreas, pituitary and gonads. Histopathological examinations were made in the control and the high-dose group.
Other examinations:
no post-exposure recovery group
Details on results:
Result (carcinogenicity): negative
With the exception of an increased kidney/body-weight ratio in female rats exposed to ca. 8.2 mg/L (2000 ppm) MMA there were no effects on organ body weight ratios. Histopathological examination of the tissues of exposed rats showed no compound related abnormalities or lesions. The change in kidney/body-weight ratio in the females treated at ca. 8.2 mg/L (2000 ppm) is considered to be a functional adaptation in response to the significantly reduced water intake.
Dose descriptor:
NOAEL
Effect level:
>= 90.3 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: no effects observed
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
>= 193.8 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: no effects observed
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
>= 2 000 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: no effects observed
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Species:
other: human/ EtOH: consumption of alcoholic beverages (not relevant for occup. exposure or consumer products)

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Remarks:
NTP protocol
Justification for type of information:
Read across from the methacrylic metabolite donor substance
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1

3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters

4. DATA MATRIX
see attached category document, endpoint specific chapters
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
NTP protocol
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 7-8 weeks
- Weight at study initiation: males 151-155g; females 117-119g (mean weights per treatment group)
- Housing: individually
- Acclimation period: 3 weeks
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.  
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
Remarks:
Doses / Concentrations:
Males: ca. 2.05 and 4.1 mg/L (corresponding to 500 and 1000 ppm ); Females: ca. 1.03 and 2.05 mg/L (corresponding to 250 and 500 ppm)
Basis:
nominal conc.
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
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.
Details on results:
Neoplastic effects
negative

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

Body weight
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.

Hematology
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 statisticaly different by life table analysis.

Histology
Pituitary and preputial gland adenomas were significantly reduced in the male rats exposed to 1000 ppm test substance. 
Serous 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.  

A NOAEC could not be established based on nasal lesions. No significant differences of the survival rates were observed between any groups. No treatment-related tumors were observed.
Dose descriptor:
NOAEC
Effect level:
>= 2.05 mg/L air (nominal)
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)
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.



Endpoint:
carcinogenicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Remarks:
NTP protocol
Justification for type of information:
Read across from the methacrylic metabolite donor substance
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1

3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters

4. DATA MATRIX
see attached category document, endpoint specific chapters
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
NTP protocol
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males 151-155 g; females 117-119 g (mean weights per treatment group)
- Housing: individually
- Acclimation period: 3 weeks
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.  
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
Remarks:
Doses / Concentrations:
ca. 2.05 and 4.1 mg/L (corresponding to 500 and 1000 ppm)
Basis:
nominal conc.
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
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.
Details on results:
Result (carcinogenicity): negative

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

Body weight
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%).

Histology
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. 

A NOAEC could not be established based on nasal lesions. No significant differences of the survival rates were observed between any groups. No treatment-related tumors were observed.
Dose descriptor:
NOAEC
Effect level:
>= 4.1 mg/L air (nominal)
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)
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)
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Species:
other: rat & mouse (MMA)

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no data on EMA. The data gap can be covered using the category approach mentioned in chapter1.1 of the category document considering the ECHA guidance on Read Across (RAAF, ECHA 2017) as follows. Scenario 3 according to RAAF is considered as most relevant for this endpoint. The category approach is done with a high level of confidence.

 

EMA is rapidly hydrolized in the human body to methacrylic acid, MAA, and ethanol, EtOH (see chapter Toxicokinetics and Category Document, chapter 5.1). Due to its own rapid hydrolysis, methyl methacrylate (MMA) serves as metabolite donor substance for MAA. Thus, for this endpoint the common primary metabolic pathway of the category members (i.e. common functional groups and rapid metabolism by ester cleavage leading to the common metabolite MAA) is considered as most relevant aspect of the category approach. Qualitatively, this aspect can be categorized as “(Bio) transformation to common compound(s)”. The category approach is used with a high level of confidence, especially as the carcinogenic potential of MAA, MMA and EtOH was comprehensively evaluated in an EU ESR (MAA), EU RA (MMA) and a SIDS Initial Assessment Report (EtOH), respectively.

 

Data

Oral

EU ESR on MMA concluded: “An early 2-year chronic study on dogs and rats treated orally with MMA revealed no adverse effect other than a lower body weight gain in high-dose dogs and elevated kidney weights in high-dose female rats (Borzelleca et al., 1964). In this study two male and two female dogs received gelatin capsules with 10, 100 and 1000 ppm MMA dissolved in corn oil. The high- dose was reduced to 500 ppm on day 2, 0 ppm on day 3-13 and 300 ppm on day 14 due to vomiting, and then increased to 1200 ppm at week 5 and to 1400 ppm at week 7 to 1500 ppm at week 9. 25 male and 25 female rats were administered with 6, 60 and 2000 ppm MMA in the drinking water, the low and medium doses increased to 7 and 70 ppm after five months.

These studies on dogs and rats revealed no increase of neoplastic lesions. However the reliability of these studies is limited due to their non-conformance to current carcinogenicity test guidelines (e.g., histopathological examination was performed on a limited number of organs).”

 

Inhalation

EU ESR on MMA concluded: “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.”

Not in this dataset:)“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 by 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.”

Evaluations for the metabolites/ metabolite donor substance

In the case of MMA the EuRA concluded: “There is no relevant concern on carcinogenicity in humans and animals. Epidemiology data on increased tumour rates in exposed cohorts were of limited reliability and can not be related to MMA as the solely causal agent. Therefore there are no reasons to assume that MMA should be considered to be carcinogenic in humans.”

In the case of MAA, the primary metabolite also of EMA, the EU ESR concluded “There are no data on carcinogenicity from methacrylic acid itself; from methyl methacrylate data, there is no concern on carcinogenic properties of methacrylic acid.” In the case of EtOH, OECD (2004) concluded that a carcinogenic hazard of EtOH does not exists from occupational exposure or use of EtOH in consumer products with exception of alcoholic beverages, although evidence is restricted to epidemiological studies with focus on theb impact of alcoholic beverages.

Also for the alcohol metabolites of the category members, there is no indication of a carcinogenic potential for exposures typical for a chemical, i.e. with exemption of alcoholic beverages in the cas of ethanol. 

In the case of EtOH, OECD (2004) concluded in their SIAR SIDS Initial Assessment Report for Ethanol that a carcinogenic hazard of EtOH does not exists from occupational exposure or use of EtOH in consumer products with exception of alcoholic beverages, although evidence is restricted to epidemiological studies with focus on theb impact of alcoholic beverages.

Evaluations for EMA

As there is no concern for mutagenic or genotoxic potential for EMA and there is no concern for cancer for its metabolites or metabolite donor substances MAA/ MMA and EtOH, there is equally no concern for carcinogenicity of EMA.

Justification for classification or non-classification

As there is no concern for mutagenic or genotoxic potential for EMA and there is no concern for cancer for its metabolites or metabolite donor substances MAA/ MMA and EtOH, there is equally no concern for carcinogenicity of EMA. Accordingly, EMA has not to be classified for this hazard.