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EC number: 219-674-4 | CAS number: 2495-37-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1 June 2012 to 21 July 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- GLP.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- adopted 22 March 1996.
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- Benzyl methacrylate
- EC Number:
- 219-674-4
- EC Name:
- Benzyl methacrylate
- Cas Number:
- 2495-37-6
- Molecular formula:
- C11H12O2
- IUPAC Name:
- benzyl methacrylate
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- Identity : Benzyl methacrylate
Alternative names : VISIOMER® BNMA; Benzylmethacrylat
CAS number : 2495-37-6
EINECS number : 219-674-4
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- A total of 90 Sprague Dawley [Crl:CD(SD)BR] rats (45 males and 45 virgin females), 7 to 8 weeks old and weighing 211-232 g for males and 135-199 g for females, were received from Charles River Italia S.p.A., Calco (Lecco), Italy.
After arrival the weight range for each sex was determined and the animals were temporarily identified within the cage by means of a coloured mark on the tail. A health check was then performed by a veterinarian.
An acclimatisation period of 14 days was allowed before the start of treatment, during which time the health status of the animals was assessed by thorough observations.
Animal room controls were set to maintain temperature and relative humidity at 22°C 2°C and 55% 15% respectively; actual conditions were monitored, recorded and the records retained. No relevant deviations from these ranges were recorded during the study. There were approximately 15 to 20 air changes per hour and the rooms were lit by artificial light for 12 hours each day.
In-life data from: 24 May 2012 to 21 July 2012
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- The test item was administered orally by gavage at a dose volume of 5 mL/kg body weight. Control animals received the vehicle alone at the same dose volume.
The required amount of Benzyl methacrylate was suspended in the vehicle (corn oil) and brought to the final volume appropriate for each concentration (concentrations of 10, 35 and
100 mg/mL) and kept under magnetic stirrer at room temperature prior to use and until the time of dosing of the last animal.
The formulations were prepared daily and the concentrations were calculated and expressed in terms of test item as supplied. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prior to commencement of treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable (content check and homogeneity). Results of the analyses were within the limits of acceptance.
The stability was found to be 24 hours at room temperature in the concentration range of 10 to 100 mg/mL.
Samples of the formulations prepared on Week 1 and last Week were also analysed to check the concentration and homogeneity. Results of the analyses were within the limits of acceptance.
Chemical analysis was carried out by the Analytical Chemistry Department at RTC according to a validated method (RTC Study No. 90820), in the range from 1 to 200 mg/mL. The software used for this activity was the Empower® Pro build No. 2154. - Duration of treatment / exposure:
- Males
Animals were dosed once a day, 7 days a week, for 2 consecutive weeks prior to pairing and thereafter through the day before necropsy.
Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
Females
Animals were dosed once a day, 7 days a week, for 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum (the day before sacrifice).
Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
During the post coitum period, dose volumes were calculated according to individual body weight on Days 0, 7, 14 and 20 post coitum and on Day 1 post partum. Thereafter individual dose volumes remained constant. - Frequency of treatment:
- once a day
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 175 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 3 groups comprised 10 male and 10 female rats received the test item at the dose levels of 50, 175 and 500 mg/kg/day. A similary constituted group of
animals received the vehicle alone (corn oil) and acted as control. - Control animals:
- yes
- Details on study design:
- The oral route was selected as it is a possible route of exposure of the test item in man.
Dose levels of 50, 175 and 500 mg/kg/day were selected by the Sponsor based on information from previous non GLP compliant studies (RTC Study nos.: 90830EXT and 90840EXT). - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- Mortality
Throughout the study, all animals were checked early in each working day in the morning and in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.
Clinical signs
Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical signs were recorded. Observations were performed approximately at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions.
Clinical observations (Functional Observation Battery Tests)
Once before commencement of treatment and once a week thereafter, each animal was given a detailed clinical examination.
Each animal was removed from the home cage and observed in an open arena.
The tests included observation of changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypies or bizarre behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern).
All observations were recorded for individual animals.
Animals were examined in an open arena for a minimum of three minutes.
Grip strength and sensory reactivity to stimuli
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group for evaluation of sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli); an assessment of grip strength was also performed. For males the tests were performed on Day 29 of the study and for females on Day 3 post partum.
Motor activity assessment (MA)
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group and the motor activity was measured (at least 5 minutes) by an automated activity recording device. Measurements were performed using a computer generated random order. For males the tests were performed on Day 29 of the study and for females on Day 3 post partum.
Body weight
Males were weighed on the day of allocation to treatment groups, on the day of treatment commencement, weekly thereafter and at termination.
Females were weighed on the day of allocation to treatment groups, on the day of treatment commencement, weekly thereafter until pairing and on Days 0, 7, 14 and 20 post coitum. Dams were also weighed on Days 1 and 4 post partum.
Food consumption
The weight of food consumed by each cage of males and females was recorded weekly, where possible, during the pre-mating period following allocation. Individual food consumption for the females was measured on Days 7, 14 and 20 post coitum starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum
Clinical pathology investigations
As a part of the sacrificial procedure, samples of blood were withdrawn under isofluorane anaesthesia from the abdominal vena cava from 5 males and 5 females (females with viable litters) randomly selected from each group, under condition of food deprivation.
The blood samples collected were divided into tubes as follows:
EDTA anticoagulant: for haematological investigations
Heparin anticoagulant : for biochemical tests
Citrate anticoagulant : for coagulation tests
The measurements performed on blood samples are listed below:
Haematology
Haematocrit
Haemoglobin
Red blood cell count
Reticulocyte count
Mean red blood cell volume
Mean corpuscular haemoglobin
Mean corpuscular haemoglobin concentration
White blood cell count
Differential leucocyte count
- Neutrophils
- Lymphocytes
- Eosinophils
- Basophils
- Monocytes
- Large unstained cells
Platelets
Coagulation tests
Prothrombin time
Clinical chemistry
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Gamma-glutamyltransferase
Urea
Creatinine
Glucose
Triglycerides
Bile acids
Phosphorus
Total bilirubin
Total cholesterol
Total protein
Albumin
Globulin
A/G Ratio
Sodium
Potassium
Calcium
Chloride
- Sacrifice and pathology:
- Parental animals were killed by exsanguination under isofluorane anaesthesia
Parental males:
Males were sacrificed after completion of the mating period after 33 days of treatment.
Parental females:
The females with live pups were killed on Day 4 post partum
Necropsy
The clinical history of the males and females of the parental generation was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices).
Changes were noted, the requisite organs weighed and the required tissue samples preserved in fixative and processed for histopathological examination
Females:
All females were examined also for the following:
a) external and internal abnormalities;
b) number of visible implantation sites (pregnant animals);
c) number of corpora lutea (pregnant animals).
Organ weights
From all animals completing the scheduled test period, the organs were dissected free of fat and weighed.
The ratios of organ weight to body weight were calculated for each animal.
Tissues fixed and preserved
Samples of all the tissues were fixed and preserved in 10% neutral buffered formalin (except testes and epididymides which were fixed in modified Davidson's fluid and preserved in 70% ethyl alcohol).
Histopathological examination
After dehydration and embedding in paraffin wax, sections of the tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin.
In addition, the testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS). The morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed.
The examination was restricted as detailed below:
a) Tissues specified in section 4.5.6 from 5 males and 5 females randomly selected (animals evaluated for clinical pathology) in the control and high dose groups killed at term.
b) All abnormalities in all groups - Statistics:
- Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data.
The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the non-parametric version of the Williams test.
The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Mortality and fate of females
No mortality occurred throughout the study.
All females proved to be pregnant.
The number of females with live pups on Day 4 post partum was 10 both in the control and in all treated groups.
Clinical signs and clinical observations (Functional Observation Battery Tests)
No relevant clinical signs were observed throughout the study in all treated animals of both sexes.
Neurotoxicity assessment (removal of animals from the home cage and open arena)
Observation of animals at removal from the cage and in an open arena (neurotoxicity assessment) did not reveal changes attributable to the test item.
Body weight and body weight gain
No relevant differences in body weights were recorded in animals of both sexes compared to the control group, throughout the study.
Food consumption
Food consumption was, in general, comparable between control and treated groups.
Motor activity and sensory reaction to stimuli
No relevant differences were noted in all parameters investigated between control and treated groups.
Haematology
No changes of toxicological significance were recorded.
No significant change was recorded in the coagulation test.
Clinical chemistry
The alteration (decrease in cholesterol level) noted in males receiving 500 mg/kg/day could not be conclusively attributed to treatment since it was observed in only one sex.
Terminal body weight and organ weights
Terminal body weight was unaffected by treatment in both sexes.
Changes noted in the absolute and relative organ weights were of low magnitude and no histological findings were observed at microscopic examination, therefore they were considered of no toxicological relevance.
Macroscopic observations
No treatment-related changes were noted.
Microscopic observations
No treatment-related changes were noted.
In addition seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and no alterations were noted.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- On the basis of the results obtained in this study, 500 mg/kg/day could be considered the NOAEL (No Observed Adverse Effect Level) for animals of both sexes.
- Executive summary:
Study design
The toxic effects on rats of both sexes after repeated oral dosing with Benzyl methacrylate, as well as on effects of the test item on male and female reproductive performance, such as gonadal function, conception, parturition and early lactation of the offspring were investigated.
The vehicle was corn oil. All doses were administered at a constant volume of 5 mL/kg body weight.
Group
Number
Treatment
(mg/kg/day)
Number of animals
1
2
3
4
0
50
175
500
10M+10F
10M+10F
10M+10F
10M+10F
Males were treated for 2 weeks prior to pairing and during pairing with females until the day before necropsy, for a total of 33 days.
Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 3post partum.
The following investigations were performed in all groups: body weight, clinical signs (including neurotoxicity assessment, motor activity and sensory reaction to stimuli), food consumption, clinical pathology investigations (haematology and clinical chemistry), macroscopic observations, organ weights and histopathological examination.
The histopathological examination was performed only on control and high dose groups (five animals/sex/group selected randomly). It included identification of the stages of the spermatogenic cycle in five males.
Mortality
No mortality occurred throughout the study.
Clinical signsand clinical observations (Functional ObservationBatteryTests)
No relevant clinical signs were observed throughout the study in all treated animals of both sexes.
Neurotoxicity assessment (removal of animals from the home cage and open arena)
Observation of animals at removal from the cage and in an open arena (neurotoxicity assessment) did not reveal changes attributable to the test item.
Body weight and body weight gain
No relevant differences in body weights were recorded in animals of both sexes compared to the control group, throughout the study.
Food consumption
Food consumption was, in general, comparable between control and treated groups.
Motor activity and sensory reaction to stimuli
No relevant differences were noted in all parameters investigated between control and treated groups.
Haematology
No changes of toxicological significance were recorded.
No significant change was recorded in the coagulation test.
Clinical chemistry
The alteration (decrease in cholesterol level) noted in males receiving 500 mg/kg/day could not be conclusively attributed to treatment since it was observed in only one sex.
Terminal body weight and organ weights
Terminal body weight was unaffected by treatment in both sexes.
Changes noted in the absolute and relative organ weights were of low magnitude and no histological findings were observed at microscopic examination, therefore they were considered of no toxicological relevance.
Macroscopic observations
No treatment-related changes were noted.
Microscopic observations
No treatment-related changes were noted.
In addition seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and no alterations were noted.
Conclusions
On the basis of the results obtained in this study, 500 mg/kg/day could be considered the NOAEL (No Observed Adverse Effect Level) for animals of both sexes.
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