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EC number: 225-969-9 | CAS number: 5188-07-8
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- First day of treatment: 13 April 2004. Experimental completion date: 16 June 2004
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
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)
- Deviations:
- yes
- Remarks:
- 4-week premating treatment instead of 2 weeks
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Sodium methanethiolate
- EC Number:
- 225-969-9
- EC Name:
- Sodium methanethiolate
- Cas Number:
- 5188-07-8
- Molecular formula:
- CH4S.Na
- IUPAC Name:
- sodium methylsulfanide
- Details on test material:
- Test substance: SODIUM METHYLMERCAPTIDE
CAS Number : 5188-07-8
Supplier: Arkema SA
Batch number : SMM33 0050-7
Purity : 32.9% solution in water
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Animals:
- Breeder: Charles River Laboratories France, L'Arbresle, France.
- Age/Weight: at the beginning of the treatment period, the males were 6 weeks old (body weight range: 183 g to 221 g), the females were 8 weeks old (body weight range: 183 g to 232 g).
- Acclimation: 7 days before the beginning of the treatment period.
Environmental conditions:
- temperature : 22 ± 2°C
- relative humidity : 50 ± 20%
- light/dark cycle : 12h/12h (7:00 - 19:00)
- ventilation : approximately 12 cycles/hour of filtered, non-recycled air.
Housing: Individually in suspended wire-mesh cages. Prior to delivery and during lactation, the animals were housed individually in polycarbonate cages.
Food and water:
- food: A04 C pelleted maintenance diet (SAFE, Villemoisson, Epinay-sur-Orge, France), ad libitum
- water: tap water (filtered with a 0.22 µm filter) ad libitum
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Control of the stability: before the start of treatment
- Control of the concentrations: on weeks 1, 4 and 8 - Duration of treatment / exposure:
- . for the males, throughout the pre-mating period (28 days), during the mating and post-mating periods until final sacrifice (approximately 8 weeks in total),
. for the females, throughout pre-mating (28 days) and mating periods, during pregnancy and lactation, until day 4 post-partum inclusive (between 8 and 9 weeks). - Frequency of treatment:
- once a day, 7 days/week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
5, 15, 45 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: none
Examinations
- Observations and examinations performed and frequency:
- Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals.
- morbidity and mortality checked twice daily during treatment period and once daily on other days; morbid rats sacrificed (necropsy)
- general clinical observations at least once daily
- body weight recorded on day 1 of treatment period and then once weekly
- food consumption determined once weekly (not in males during mating period)
Detailed clinical observations and neurobehavioral tests were conducted at designated intervals to assess behavior, main functions and reflexes and to measure motor activity over a 60-minute period.
- detailed clinical observations once weekly on a blind basis; rats observed in the cage, in the hand and in a standard arena
- shortly before terminal sacrifice, the reactivity to manipulations or different stimuli was checked in 5 males and 5 females of each group (randomization) as well as the motor activity over a 10 minute period (automatically recorded)
Blood and urine samples were collected from five males and five females at the end of the pre-mating period (ca. 4.5 weeks of treatment) for hematology, blood biochemistry and urinalysis investigations.
- Hematology: Erythrocytes (RBC), Hemoglobin (HB), Mean cell volume (MCV), Packed cell volume (PCV), Mean cell hemoglobin concentration (MCHC), Mean cell Hemoglobin (MCH), Thrombocytes (PLAT), Leucocytes (WBC), Differential white cell count with cell morphology, Prothrombin time, Activated partial thromboplastin time (APTT), Fibrinogen (FIB).
- Blood biochemistry: Sodium (Na+), Potassium (K+), Chloride (Cl-), Calcium (Ca++), Inorganic phosphorus (I.PHOS), Glucose (GLUC), Urea (UREA), Creatinine (CREAT), Total bilirubin (TOT.BIL.), Total proteins (PROT), Albumin (ALB), Albumin/globulin ratio (A/G), Total cholesterol (CHOL), Triglycerides (TRIG), Alkaline phosphatase (ALP), Aspartate aminotransferase (ASAT), Alanine aminotransferase (ALAT), Bile acids (BILAC).
- Urinalysis: Volume (VOLUME), pH, Specific gravity (SP.GRAV), Proteins (PROT), Glucose (GLUC), Ketones (CETO), Bilirubin (BILI), Nitrites (NITR), Blood (BLOOD), Urobilinogen (UROB), Cytology of sediment. - Sacrifice and pathology:
- At final sacrifice, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for five males and five females of the control and high-dose groups. Additionally, a microscopic examination of the spleen was performed for animals of the low and mid-dose groups. Furthermore, the spleen of animals of the control and the high-dose group was stained using Perls staining to confirm the nature of the observed pigment (hemosiderin) and for a more accurate evaluation of the severity of hemosiderin deposition.
- Macroscopic post-mortem examination: at termination (or moribund rats during treatment period).
- Organ weights: Adrenals, Brain, Epididymides, Heart, Kidneys, Liver, Spleen, Testes, Thymus.
- Microscopic examination:
. as tabulated in OECD guideline 422 for five males and five females of the control and high-dose groups killed at the end of the treatment period,
. macroscopic lesions of all the animals of the low- and intermediate-dose groups killed on completion of the treatment period.
. spleen of five males and five females of the low and intermediate dose groups
. spleen, stained with Perls staining, of five males and five females of the control and high-dose groups. - Statistics:
- - mean quantitative values compared by one-way analysis of variance and Dunnett test; proportions are compared by the Fisher exact probability test
- hematology, biochemistry, urine analysis and organ weight: test for normality of distribution, Bartlett test (homogeneity of variances between groups), Dunn test (not homogeneous) or Dunnett test - *: p<0.05; **: p<0.01
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL EXAMINATION
- Mortality: there were no deaths in any group.
- Clinical signs:
. 45 mg/kg/d: hypotonia was transiently observed in all males and females during the whole dosing period, ataxia was observed at detailed clinical observations in 4 males and in one female during week 5 or 6 of dosing, ptyalism was observed in most males and females a few days after the beginning of the study until the end of dosing.
. 5 and 15 mg/kg/d: no clinical sign was noted.
- Body-weight :
. 45 mg/kg/d: in the males, the group mean body weight gain was statistically significantly lower during the first week of dosing (days 1 to 8: 45 g vs. 55 g, -18%, p<0.01) and remained marginally lower during the dosing period. In the females, the group mean body weight gain was marginally lower during the premating period.
. 5 and 15 mg/kg/d: no effect was noted.
- Food consumption:
. 45 mg/kg/d: in the males, the food consumption was marginally lower during the whole study.
. 5 and 15 mg/kg/d: no effect was noted.
- Haematology:
. 45 mg/kg/d: slightly lower (-6%) hemoglobin concentration was recorded in both males and females. This was associated, in the males with lower mean cell volume (-4%), and in the females with lower mean cell hemoglobin concentration (-4%), lower red blood cell count (-11%), and lower packed cell volume (-9%).
- Blood biochemistry: no relevant changes were noted in blood biochemical parameters at any dose-levels.
- Urinalysis: the urinalysis parameters were unaffected by the treatment.
PATHOLOGY
- Necropsy: no substance related effect at any dose-levels.
- Organ-weights:
. 45 mg/kg/d: higher absolute (+22%, +49%) and relative (+33%, +57%)spleen weights were noted in the males and females
. 15 and 5 mg/kg/d: no substance related effect.
- Microscopic examination:
. 45 mg/kg/d: increased incidence and/or severity of extramedullary hematopoiesis and hemosiderosis in the spleen of both males and females and sinusoidal ectasia in most of the males. Extramedullary hematopoiesis was observed with a higher incidence (but a marginally higher severity) in the liver of females given 45 mg/kg/day; this was associated with greenish pigment in a few Kuppfer's cells in 1/5 males and 2/5 females.
. 15 and 5 mg/kg/d: no substance related effect.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 15 mg/kg bw/day (nominal)
- Sex:
- male/female
- Dose descriptor:
- LOAEL
- Effect level:
- 45 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Hematological and spleen changes (regenerative anemia)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
CHEMICAL ANALYSIS OF THE DOSAGE FORMS
- Stability: Satisfactory stability over a 9-day period at
+4°C.
- Concentration: satisfactory agreement between the nominal
and actual concentrations
Applicant's summary and conclusion
- Conclusions:
- The NOAEL and the LOAEL of sodium methanethiolate in rats were considered to be 15 and 45 mg/kg bw/day, respectively.
- Executive summary:
In a combined repeated-dose/reproductive/developmental toxicity screening study (OECD TG 422), Sprague-Dawley rats (10/sex/dose) were administered 0, 5, 15 or 45 mg/kg bw/day of sodium methanethiolate in water by gavage daily for 8-9 weeks at a volume of 5 ml/kg. There was no mortality or changes in blood biochemistry values or urinalysis parameters. There were no clinical signs of toxicity or body weight or food consumption effects observed in the 5 or 15 mg/kg bw/day groups. At 45 mg/kg bw/day, clinical signs observed included transient low muscle tone in males and females, incoordination of muscles in four males and one female at weeks 5 or 6 and excessive salivation in most males and females beginning a few days into the study and continuing though the end of dosing. The group mean body weight gain of the males in the 45 mg/kg bw/day group was significantly lower (19%) during the first week of dosing and remained marginally reduced during the dosing period relative to the control group. In the females exposed to 45 mg/kg bw/day, the mean group body weights were marginally reduced during premating and significantly reduced during the first week of gestation in comparison to the control group. The food consumption values were marginally reduced throughout the study for the 45 mg/kg bw/day males but not the females. Decreased hemoglobin concentration was observed in the males and females of the 45 mg/kg/day dose group. This was associated with reduced mean cell volume in the males and with decreased mean cell hemoglobin concentration, red blood cell count and packed cell volume in the females. At necropsy, there were no macroscopic treatment-related effects observed in any dose group. There were no organ weight effects or microscopic effects observed in the 5 or 15 mg/kg bw/day dose groups. Higher absolute and relative spleen weights were observed for the male (22 and 33% increased, respectively) and female (49 and 57% increased, respectively) rats exposed to 45 mg/kg bw/day. Increased incidence and/or severity of extramedullary hematopoiesis and hemosiderosis in the spleen of both male and female rats and sinusoidal ectasia in the male rats was observed at 45 mg/kg bw/day (p<0.01). In the 45 mg/kg bw/day females, a higher incidence of extramedullary hematopoiesis in the liver was observed that was associated with greenish pigment in a few Kupffer’s cells. The NOAEL and the LOAEL of sodium methanethiolate in rats were considered to be 15 and 45 mg/kg bw/day, respectively.
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