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Administrative data

Description of key information

Repeated dose toxicity: oral

Oral administration of 1500 mg/kg/day (1.5 g/kg/day) test substance for 90 days did not cause any adverse effects or mortality. Body weight and estimated food consumption were not affected. No hematological or clinical chemical alterations were noted. Renal histology of treated animals was normal.Thus,the no-observed adverse effect level (NOAEL) of test substance in this 90 day gavage study was determined to be 1500 mg/kg/day.

Repeated dose toxicity: inhalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance Dimethyl sulfone, methanesulfonylmethane (67-71-0) which is reported as 0.0073581053 mmHg. As the particle size distribution of the substance dimthyl sulphone, the majority of the particles were found to be in the size of 150 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical the particle size distribution is highly unlikely. Therefore this study is considered for waiver.

 

Repeated dose toxicity: dermal

The acute toxicity value for Dimethyl sulfone, methanesulfonylmethane (67-71-0) (as provided in section 7.2.3) is >5000 mg/kg body weight. The substance was also found to be not irrtating to skin. Also, given the use of the chemical as dietary supplements used in a variety of conditions including pain, inflammation,allergies, arthritis, parasitic infections and the maintenance of normal keratin levels in hair, skin and nails.; repeated exposure by the dermal route is unlikely. Thus, it is expected that dimethyl sulphone shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that dimethyl sulphone shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Data is from peer-reviewed journal
Qualifier:
no guideline available
Principles of method if other than guideline:
The objective of this study was to evaluate the subchronic toxicity of test substance in rats.
GLP compliance:
not specified
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source of test material: Cardinal Nutrition, Inc.(OptiMSMTM Vancouver, WA, USA)
- Lot/batch No.of test material: #99121.11
- Expiration date of the lot/batch: no data
- Purity test date: no data

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: no data
- Specific activity: no data
- Locations of the label: no data
- Expiration date of radiochemical substance: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:no data
- Stability under test conditions: no data
- Solubility and stability of the test substance in the solvent/vehicle: no data
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: no data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:no data
- Preliminary purification step (if any): no data
- Final dilution of a dissolved solid, stock liquid or gel: no data
- Final preparation of a solid: no data

FORM AS APPLIED IN THE TEST (if different from that of starting material): no data

OTHER SPECIFICS: no data
Species:
rat
Strain:
Wistar
Remarks:
Crl:(WI)BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Hungary Ltd (Budapest, Hungary)
- Age at study initiation: 5 weeks old
- Weight at study initiation: 84-108 g
- Fasting period before study: Overnight
- Housing: Rats were housed two per cage of the same sex in Type II macrolon cages.
- Diet (e.g. ad libitum): standardized rat and mouse diet VRF-1 (Altromin GmbH, Lage, Germany)
- Water (e.g. ad libitum): tap water; ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±30 °C
- Humidity (%): between 30 and 80%
- Air changes (per hr): 15 times per h
- Photoperiod (hrs dark / hrs light): 12-h light/dark cycles

IN-LIFE DATES: From: To: No data
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 1500 mg/kg of MSM in a volume of 10 ml/kg distilled water.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: 1.5 g/kg (1500 mg/kg)
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): A0010699
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Dose / conc.:
1 500 other: mg/kg
No. of animals per sex per dose:
Total: 80 rats
40 males and 40 females
Control animals:
yes
Details on study design:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes (measured weekly)
Mean food consumption was calculated from the amount consumed in 10 cages (20 animals)

FOOD EFFICIENCY:
- 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 5 male & 5 female rats
- Parameters that were examined:
Erythrocyte (RBC), leukocyte (WBC) and platelet (PLT) counts, hematocrit (Hct) and mean corpuscular hemoglobin (MCH) using a Coulter AcT8 cytometer (Coulter Diagnostics, FL, USA).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters that were examined: serum enzymes, lipid profile,serum proteins, albumin and blood chemistries

URINALYSIS: Yes
- Time schedule for collection of urine: prior to treatment and on week 7
- Metabolism cages used for collection of urine: No data
- How many animals: 5 male & 5 female rats
- Animals fasted: No data
- Parameters that were examined: Appearance,volume, specific gravity, pH, protein, glucose and blood

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: No data

OTHER
DETAILED MORTALITY OBSERVATIONS: Yes
- Time schedule: Twice daily
Sacrifice and pathology:
Necropsy was performed 91 days after initiation of treatment.
GROSS PATHOLOGY: Yes
A full gross necropsy was performed. The following organs were weighed, examined: liver, kidneys, adrenals, left testicle, spleen, brain, thymus, heart, mesenteric lymph nodes, submandibular lymph nodes, stomach, duodenum, pancreas, lungs, pituitary, trachea, esophagus, thyroids, parthyroids, left epididymis, prostate, uterus and ovaries, right testes and epididymis, bone marrow.

HISTOPATHOLOGY: Yes
Statistics:
Bartlett’s test of variances was used to compare variances among treatment groups. If the variances proved to be homogeneous, one-way analysis of variance (ANOVA) was performed. If ANOVA detected significant differences (P <0.05), a Dunnett’s test for comparing treatment means with a control was used.
If the values for the treatment groups failed Bartlett’s homogeneity test, the Kruskal–Wallis non-parametric ANOVA was performed. If significant differences were found among the groups, distribution-free multiple comparisons were performed.
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical sings was observed.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No hematological alterations were measured. All hematology data were within normal limits.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No blood chemistry alterations were measured. All blood chemistry values were within normal physiologic ranges.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urinalysis was normal without glucosuria, proteinuria or hematuria.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No difference in organ weights between the two groups were observed in comparison to the control group.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological lesions were noted.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related lesions were seen in the kidneys of rats receiving the limit dose of 1500 mg/kg MSM by the oral route. There were no other treatment related histopathologic findings in any of the kidneys of the control or test substance treated males and females.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Oral administration of 1500 mg/kg/day (1.5 g/kg/day) MSM for 90 days did not cause any adverse effects or mortality. Body weight and estimated food consumption were not affected. No hematological or clinical chemical alterations were noted. No gross pathological lesions were noted. Renal histology of treated animals was normal.
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
other: No any adverse effects was observed
Remarks on result:
other: No toxic effect were observed
Critical effects observed:
no
Conclusions:
Oral administration of 1500 mg/kg/day (1.5 g/kg/day) test substance for 90 days did not cause any adverse effects or mortality. Body weight and estimated food consumption were not affected. No hematological or clinical chemical alterations were noted. Renal histology of treated animals was normal.Thus, the no-observed adverse effect level (NOAEL) of test substance in this 90 day gavage study was determined to be 1500 mg/kg/day.
Executive summary:

In a subchronic study, male and female Wistar [Crl:(WI)BR] rats (20/sex) were orally administered (via gavage) either distilled water or 1500 mg/kg/day of test substance in distilled water for 90 days. The major organs were weighed and fixed in formaldehyde for histopathological observations, and clinical chemistry parameters (i.e., serum enzymes, lipid profile,serum proteins, albumin and blood chemistries) and urinalysis parameters (i.e., appearance, volume, specific gravity, pH, protein, glucose, and blood) were analyzed. No effects on body weight, hematological parameters or histopathological lesions in organs and tissues were found. At necropsy, no gross pathological changes or differences in organ weights were noted, except for a significant increase in kidney weights of treated male rats. Histopathological examination of kidneys in both males and females did not reveal any treatment related lesions, and therefore the significant kidney weight difference was considered likely due to low within-group deviations rather than a toxicological effect. Thus, the no-observed adverse effect level (NOAEL) of test substance in this 90 day gavage study was determined to be 1500 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The data is Klimicsh 2 and from peer-reviewed journal.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Various data available for the test chemical was reviewed to determine the toxic nature of Dimethyl sulfone, methanesulfonylmethane (67-71-0) upon repeated exposure by oral route. The studies are as summarized below:

Repeated dose toxicity: oral

In a subchronic study, male and female Wistar [Crl:(WI)BR] rats (20/sex) were orally administered (via gavage) either distilled water or 1500 mg/kg/day of test substance in distilled water for 90 days. The major organs were weighed and fixed in formaldehyde for histopathological observations, and clinical chemistry parameters (i.e., serum enzymes, lipid profile,serum proteins, albumin and blood chemistries) and urinalysis parameters (i.e., appearance, volume, specific gravity, pH, protein, glucose, and blood) were analyzed. No effects on body weight, hematological parameters or histopathological lesions in organs and tissues were found. At necropsy, no gross pathological changes or differences in organ weights were noted, except for a significant increase in kidney weights of treated male rats. Histopathological examination of kidneys in both males and females did not reveal any treatment related lesions, and therefore the significant kidney weight difference was considered likely due to low within-group deviations rather than a toxicological effect. Thus, the no-observed adverse effect level (NOAEL) of test substance in this 90 day gavage study was determined to be 1500 mg/kg/day.

Supported by another study. The study was conducted to investigate the effects of test substance on the musculature of Standardbred horses. Thirty horses were randomly divided into three groups of ten animals each. Each horse was three to four years old and weighed approximately 500 kg. The first group served as control while Group 2 and 3 were treated orally with 10 and 20 g MSM/day (20 and 40 mglkg/day),respectively for twelve weeks. Each animal was thermographic at several pre-selected times for determination of body temperature variations. Blood samples were drawn initially and at weekly intervals for hematology (RBC, WBC, packed cell volume, and the types of WBC's) and serum chemistry analysis (albumin levels, alkaline phosphatase, BUN, calcium, creatinine, glucose, magnesium, phosphorus, aspartate aminotransferase, serum protein, total bilirubin, sodium, potassium, chloride, gamma-glutamyl transpeptidase, creatine kinase, albumin/globulin ratio, globulin, lipemic index, hemolytic index, and icteric index). In the treatment groups, reductions in thermal gradients were noted. No adverse effects of test substance were noted in the treatment groups. The hematological examination did not reveal any significant variations in the parameters studied that would indicate anemia, electrolyte imbalances, hepatotoxicity or renal damage. On the basis of the parameters examined, the NOAEL was considered to be 40 mg/kg body weight, the highest dose tested.

Repeated dose toxicity: inhalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance Dimethyl sulfone, methanesulfonylmethane (67-71-0) which is reported as 0.0073581053 mmHg. As the particle size distribution of the substance dimthyl sulphone, the majority of the particles were found to be in the size of 150 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical the particle size distribution is highly unlikely. Therefore this study is considered for waiver.

 

Repeated dose toxicity: dermal

The acute toxicity value for Dimethyl sulfone, methanesulfonylmethane (67-71-0) (as provided in section 7.2.3) is >5000 mg/kg body weight. The substance was also found to be not irrtating to skin. Also, given the use of the chemical as dietary supplements used in a variety of conditions including pain, inflammation,allergies, arthritis, parasitic infections and the maintenance of normal keratin levels in hair, skin and nails.; repeated exposure by the dermal route is unlikely. Thus, it is expected that dimethyl sulphone shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that dimethyl sulphone shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Based on the data available from the test chemical, Dimethyl sulfone, methanesulfonylmethane (67-71-0) not likely to exhibit repeated dose oral, dermal and inhalation toxicity. Hence the test chemical is not likely to classify as a repeated dose dermal toxicity as per the criteria mentioned in CLP regulation.

 

Justification for classification or non-classification

Based on the data available from the test chemical, Dimethyl sulfone, methanesulfonylmethane (67-71-0) not likely to exhibit repeated dose oral, dermal and inhalation toxicity. Hence the test chemical is not likely to classify as a repeated dose dermal toxicity as per the criteria mentioned in CLP regulation.