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EC number: 200-625-0 | CAS number: 66-27-3
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from peer reviewed publication
Data source
Reference
- Reference Type:
- publication
- Title:
- Collaborative work to evaluate toxicity on male reproductive organa by repeated dose studies two week and 4 week administration study of in rats Methyl Methansulfonate (MMS)
- Author:
- Shigenari Ozawa, Ryohei Yokoi, Tsuyoshi Kitamura, Kazuya Kuriyama, Kazuo Kobayashi and Nobuo Shibata
- Year:
- 2 000
- Bibliographic source:
- Journal of Toxicological Sciences, Vol. 25, special issue, 155 – 162, 2000
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Refer below principle
- Principles of method if other than guideline:
- Subacute repeated dose oral toxicity study of Methyl Methansulfonate (MMS) was performed in Sprague – Dawley Rat.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Methyl methanesulphonate
- EC Number:
- 200-625-0
- EC Name:
- Methyl methanesulphonate
- Cas Number:
- 66-27-3
- Molecular formula:
- C2H6O3S
- IUPAC Name:
- methyl methanesulfonate
- Test material form:
- other: Liquid
- Details on test material:
- - Name of test material: Methyl Methanesulphonate (MMS)
- Molecular formula: C2H6O3S
- Molecular weight: 110.1324 g/mol
- Substance type: Organic
- Physical state: Solid
- Purity: 99.9%
- Impurities (identity and concentrations): 0.01%
Constituent 1
- Specific details on test material used for the study:
- - Name of test material: Methyl Methanesulphonate (MMS)
- Molecular formula: C2H6O3S
- Molecular weight: 110.1324 g/mol
- Substance type: Organic
- Physical state: Solid
- Purity: 99.9%
- Impurities (identity and concentrations): 0.01%
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- No data
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc. (Astugi, Japan)
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals were housed in barrier system.
- Diet (e.g. ad libitum): Laboratory animals diet ( gamma irradiated CE-2, CLEA Japan, Inc., Tokyo, Japan), ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: Yes, duration not mention.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.8 to 23.6˚C
- Humidity (%): 43.5 to 55.8%
- Air changes (per hr): 16.3 air changes / hour
- Photoperiod (hrs dark / hrs light): 12 hr light/dark cycle
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- No data
- Vehicle:
- water
- Remarks:
- Distilled water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Methyl Methansulfonate (MMS) was dissolved in distilled water to give a dose level of 0, 20 or 40 mg/Kg bw/day.
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water
- Concentration in vehicle: 0, 20 or 40 mg/kg body weight /day
- Amount of vehicle (if gavage): 5 ml/kg body weight
- Lot/batch no. (if required): No data available
- Purity: No data available - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No data available
- Duration of treatment / exposure:
- 2 weeks
- Frequency of treatment:
- Once daily
Doses / concentrations
- Remarks:
- 0, 20 or 40 mg/kg body weight /day
- No. of animals per sex per dose:
- Total: 30
0 mg/kg body weight /day: 10 male
20 mg/kg body weight /day: 10 male
40mg/kg body weight /day: 10 male - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Doses were selected on the basis of results of the 4 week micronucleus study. In the preliminary study, a 4 week repeated administration of 30 mg/kg of MMS cause degeneration of the seminiferous tubules of the testis and sloughing of germ cells into the lumen in all rats. Because of overt toxicity 20 and 40 mg/kg dose were selected for present study.
- Rationale for animal assignment (if not random): No data available
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available - Positive control:
- No data
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included: Survival was observed.
DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available
BODY WEIGHT: Yes
- Time schedule for examinations: Once a week
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY: No data available
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available
OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available
CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available
URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available
NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available
OTHER:
Organ weights were taken: Testes and epididymis were weighted - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, animals were sacrificed after inhalation with carbon dioxide and necropsied on the day of final administration. Main organ like brain, heart, lungs, liver, spleem and kidneys were fixed in 10 % buffered formalin and preserved. Testes and epididymis were weighed and fixed in formalin acetic acid for 5 days before final fixation in 10% buffered formalin. They were then embedded in paraffin, sectioned and stained with hematoxylin and eosin, periodic acid Schiff and examined.
HISTOPATHOLOGY: Yes
Brain, heart, lungs, liver, spleen, kidneys, testes and epididymis were examined microscopically - Other examinations:
- Stags of spermatogenesis were examined. PAS stained sections of the left testes were used to identify the spermatogonic stages. For quatitative evaluation, 3 spermatogonic stages (II-III, VII and XII) were selected for stage analysis with 3 seminiferous tubules of each stage of each rats. The cell types were also recognized.
- Statistics:
- Statistical analysis was performed by using F- test for homogeneity of variance. With homogenous data student’s t- test were used. Where variance was not homogenous Aspin – Welch method was employed. Comparisons among 3 groups, homogeneity of variance was tested using Barlett’s method. With homogenous data one – way analysis of variance was used. Kruskal – Wallis procedures for non-parametric analysis were used. For significant inter-group difference Dunnett multiple comparison test or Dunnett’s rank test were applied. The level of statistical significance of difference was set at less than 0.05.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY:
Mortality: No effect on survival were observed in treated male rat as compared to control.
Clinical signs: No Clinical signs of toxicity were observed in treated male rat as compared to control.
BODY WEIGHT AND WEIGHT GAIN: When treated with 40 mg/kg body weight/day, significant decrease in body weight was observed from day 8 of treatment in treated male rat as compard to control.
No significant body weight change was observed in 20 mg/kg body weight/day treated male rat as compared to control.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No significant changes in food consumtion was observed in 20 mg/Kg bw/day dose group as compared to controls. There was a tendency of decrease on day 2 of treatment in the 40 mg/Kg group and significant differences between 40 mg/Kg bw/day and control group were observed from day 9 of treatment
FOOD EFFICIENCY: No data available
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
OPHTHALMOSCOPIC EXAMINATION: No data available
HAEMATOLOGY: No data available
CLINICAL CHEMISTRY: No data available
URINALYSIS: No data available
NEUROBEHAVIOUR: No data available
ORGAN WEIGHTS: When treated with 40 mg/kg body weight/day, significant decrease in absolute testes and epididymides weight was observed in treated male rat as compard to control. However, there was no significant differences in relative organ weight.
GROSS PATHOLOGY: Slight atrophy of testes was observed in 40 mg/kg body weight/day as compared to control and spermatic granuloma was observed in the right epididymis in one animal of control group. No other gross abnormalities were observed.
HISTOPATHOLOGY: NON-NEOPLASTIC: Slight atrophy of seminiferous tubules (1/10), decrease (8/10) and exfoliation (3/10) of germ cells, vacuolar degeneration of sertoli cells of testes in and moderate cell debris in caput, slight caudal epididymal ducts, decrease of permatids (elongated) and spermatic grnuloma of epididymis was observed in 40 mg/kg body weight/day dose group.
Atrophy of seminiferous tubules (1/10) and dilatation of the smeiniferous tubules (1/10), Slight vacuolar degeneration of sertoli cells of testes and cell debris in caput and caudal epididymal ducts of epididymis (4/10) was observed in 20 mg/kg body weight/day as compared to control.
HISTOPATHOLOGY: NEOPLASTIC (if applicable): No data available
HISTORICAL CONTROL DATA (if applicable): No data available
OTHER FINDINGS: Stags of spermatogenesis:
Significant decrease in spermatogonia was observed in stage XII seminiferous tubules of 40 mg/kg body weight/day dose group and significant decreased in pachytene spermatocytes at stage XII were observed in 20 mg/kg body weight/day as compared to control.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No effect on survival, body weight, food consumption, organ weight, gross pathology, histopathology and Stags of spermatogenesis.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table: Organ weight of male rats treated with MMS
Dose (mg/Kg bw/day) |
No of animals |
Final BW |
Absolute organ weights |
Relative organ weights |
||
Testis |
Epididymis |
Testis |
Epididymis |
|||
Control |
10 |
389.0±31.2 |
3.31±0.24 |
0.93±0.13 |
8.59±1.13 |
2.39±0.33 |
20 |
10 |
376.7±30.7 |
3.32±0.19 |
0.82±0.04 |
8.86±0.80 |
2.18±0.22 |
40 |
10 |
332.5±27.5** |
2.89±0.39 |
0.70±0.09** |
8.76±1.47 |
2.12±0.26 |
Table: Histopathology of male rats treated with MMS
Organ |
Administration period |
2 weeks |
|||||||||||
|
Dose (mg/Kg) |
0 |
20 |
40 |
|||||||||
|
Findings/ Grade |
- |
+ |
++ |
+++ |
- |
+ |
++ |
+++ |
- |
+ |
++ |
+++ |
Testis |
Atrophy of seminiferous tubules |
10 |
0 |
0 |
0 |
9 |
1 |
0 |
0 |
9 |
1 |
0 |
0 |
|
Dilatation of seminiferous tubules |
10 |
0 |
0 |
0 |
9 |
1 |
0 |
0 |
10 |
0 |
0 |
0 |
|
Decrease of germ cells |
10 |
0 |
0 |
0 |
10 |
0 |
0 |
0 |
2 |
8 |
0 |
0 |
|
Exfoliation of germ cells |
10 |
0 |
0 |
0 |
10 |
0 |
0 |
0 |
7 |
3 |
0 |
0 |
|
Vacoular degeneration of sertoli cells |
5 |
4 |
1 |
0 |
4 |
6 |
0 |
0 |
1 |
9 |
0 |
0 |
Epididymis |
Cells debris in caput epididymal ducts |
8 |
2 |
0 |
0 |
8 |
2 |
0 |
0 |
0 |
3 |
7 |
0 |
Cells debris in caudal epididymal ducts |
9 |
1 |
0 |
0 |
8 |
2 |
0 |
0 |
4 |
6 |
0 |
0 |
|
Decrease of spermatids (elongated) |
10 |
0 |
0 |
0 |
10 |
0 |
0 |
0 |
6 |
4 |
0 |
0 |
|
Spermatic granuloma |
8 |
1 |
1 |
0 |
10 |
0 |
0 |
0 |
10 |
0 |
0 |
0 |
Applicant's summary and conclusion
- Conclusions:
- The No observed adverse effect level (NOAEL) was considered to be 20 mg/kg body weight /day when Sprague – Dawley male rats were exposed to Methyl Methansulfonate (MMS) for 2 weeks
- Executive summary:
In Repeated dose subacute oral toxicity study, male Sprague – Dawley rats were treated with Methyl Methansulfonate (MMS) at a concentration of 0, 20 or 40 mg/kg body weight/day orally by gavage for 2 weeks. The animals were observed for clinical signs, mortality, body weight changes, food consumption, gross pathology and histopathology. No effects were observed on mortality, clinical sign, body weight and food consumption at 20 mg/kg body weight/day treated rat as compared to control. However, when treated with 40 mg/kg body weight/day, significant decrease in body weight was observed from day 8 of treatment in treated male rat as compared to control and there was a tendency of decrease on day 2 of treatment in the 40 mg/Kg group and significant differences between 40 mg/Kg bw/day and control group were observed from day 9 of treatment. When treated with 40 mg/kg body weight/day, significant decrease in absolute testes and epididymides weight was observed in treated male rat as compared to control. However, there were no significant differences in relative organ weight. Slight atrophy of testes was observed in 40 mg/kg body weight/day as compared to control and spermatic granuloma was observed in the right epididymis in one animal of control group. No other gross abnormalities were observed. Slight atrophy of seminiferous tubules (1/10), decrease (8/10) and exfoliation (3/10) of germ cells, vacuolar degeneration of sertoli cells of testes in and moderate cell debris in caput, slight caudal epididymal ducts, decrease of spermatids (elongated) and spermatic grnuloma of epididymis was observed in 40 mg/kg body weight/day dose group. Atrophy of seminiferous tubules (1/10) and dilatation of the smeiniferous tubules (1/10), Slight vacuolar degeneration of sertoli cells of testes and cell debris in caput and caudal epididymal ducts of epididymis (4/10) was observed in 20 mg/kg body weight/day as compared to control. Significant decreased in spermatogoni was observed in stage XII seminiferous tubules of 40 mg/kg body weight/day dose group. Significant decreased in pachytene spermatocytes at stage XII were observed in 20 mg/kg body weight/day as compared to control. Observation made suggest the No observed adverse effect level (NOAEL) was considered to be 20 mg/kg body weight /day when Sprague – Dawley male rats were exposed to Methyl Methansulfonate (MMS) for 2 weeks.
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