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EC number: 204-317-7 | CAS number: 119-36-8
- 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
Endpoint summary
Administrative data
Description of key information
The toxicity of MeS on repeated exposure has been studied primarily by the oral route, with data acceptable for human risk assessment from studies of up to two years. Studies of shorter duration and lower reliability have been carried out by the inhalation and dermal routes. A set of studies was conducted by Webb & Hansen (1963), consisting of oral feeding studies of duration 17 weeks and 2 years in rats and studies in dogs by capsule administration of duration 59 days and 2 years. These studies did not examine all the parameters recommended in the current OECD guidelines 409 and 452, however they were conducted according to good scientific principles by US FDA and assigned Rel. 2. The chronic studies in rat and dog are therefore proposed as key studies. The same authors also conducted a 96-day dermal study in rabbits providing only limited data for assessment (Rel. 3).
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data are available
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: This is an old study (1963), predating GLP however the protocol and results were reported in adequate detail and included hematological studies, gross pathology, and limited histopathological examinations of key organs and tissues.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- MeS was blended with diet and adminstered daily for a period of 2 years.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Osborne-Mendel
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: weanling
- Weight at study initiation: ~ 50 g
- Fasting period before study: no data
- Housing: no data
- Diet: ad libitum
- Water: no data
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod: no data
IN-LIFE DATES: no data - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): every other week
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: all diets were stored in sealed cans under refrigeration
- Other: 10% additional methyl salicylate was added at time of mixing to compensate for evaporation
VEHICLE: none - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- none
- Duration of treatment / exposure:
- 2 years
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0, 0.1, 0.5, 1 and 2% (0, 50, 250, 500, and 1000 mg/kg bw/day)
Basis:
nominal in diet - No. of animals per sex per dose:
- 25/sex/dose (except for 24 males, 26 females in 2% group)
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: the data reported in the subchronic study in rats by the same authors (methyl salicylate/ dietary administration for 17 weeks in rats).
- Positive control:
- no data are available
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: The rats were weighed weekly.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No
FOOD EFFICIENCY: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 3, 11, 17 and 22 months.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10 rats/dose
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- none
- Statistics:
- not reported
- 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):
- not examined
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- 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:
- effects observed, treatment-related
- Details on results:
- CLINICAL SIGNS AND MORTALITY
Animals of the 1.0% and 2.0% groups developed rough hair coats In the high-dose group, half of the animals died by week 8 and all of the animals
died by week 49 of the study.
BODY WEIGHT AND WEIGHT GAIN:
Animals of the 1.0% and 2.0% groups had statistically significant growth inhibition.
HAEMATOLOGY
no hematological effects were observed.ORGAN WEIGHTSAverage organ weights were similar for all animals. however, relative organ to body weight
ratios for the testes of male animals and for the heart and kidneys of the female animals of the 1.0% groups were significantly increased.
GROSS PATHOLOGY
gross lesions of the pituitary gland were observed in 10 animals of the 0.5% group as compared to four animals in the control
group.In the 2% group, 29 of the 50 animals had pneumonia, which appeared to be more acute than regularly observed.
HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopically, the only induced lesion was a pronounced change in the bones of the rats on the 2.0% diet.
Cancellous bone in the metaphysis was increased as compared to same-age controls; this was observed to a moderate degree in five and a marked
degree in four of the nine bones examined from animals of the 2.0% group. Bone lesions were slight in 2 of 11 and 1 of 11 bones examined from
animals of the 1.0% and 0.5% groups, respectively. The affected bones had fewer osteoclasts, and the number was inversely proportional to the
degree of change.
HISTOPATHOLOGY: NEOPLASTIC
The data are limited:Malignant pituitary tumors occurred in 1 male and 2 female rats on the 0.5% diet. Mammary tumors occurred in females rats on
all diets. - Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see below
- Critical effects observed:
- not specified
- Conclusions:
- Under the test conditions, growth retardation and bone lesions were reported at 1.0 and 2.0% and gross pituitary lesions at 0.5% MeS in the diet. Based on this study, the NOAEL /oral/rat is 50 mg/kg body weight/day.
- Executive summary:
Webb and Hansen (1963) administered methyl salicylate in the diet to groups of male and female Osborne-Mendel rats at concentrations of 0, 0.1%, 0.5%, 1.0% or 2.0% in the diet providing doses of approximately 0, 50, 250, 500, and 1000 mg/kg bw/day for two years. All rats in the 1000 mg/kg group died by the 49th week. Body weight of both sexes was significantly decreased in the 500 and 1000 mg/kg body weight/day groups.
An increased amount of cancellous bone was present in the metaphyses in rats treated at either 500 or 1000 mg/kg body weight/day, with a more marked effect at the highest dose level. The relative testis weight of males was significantly increased as were the relative weights of the heart and kidneys of females in the 500 mg/kg body weight/day group. Gross pituitary gland lesions were increased at 250 but not 500 mg/kg bw/day compared to controls.
Based on this study, the NOAEL value is 50 mg/kg body weight/day.
Reference
The results for a supplemental study:
One male test animal died on day 11, the two others died on day 19. The females died on days 31, 40 and 71. Rough hair coat and growth inhibition was observed for all test animals, with some animals having labored respiration.
Grossly, four of the six treated rats had slight to moderate lung damage. Focal gastric hemorrhages were present in the glandular portion of three of the test animals. Bone growth was affected.
Long bones of the limbs showed reduced length and diameter compared to controls. Density of the hypophysis of long bones was increased.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Single concentration tested. No data on substance purity.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- GLP compliance:
- no
- Species:
- rat
- Strain:
- other: Alderley Park
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Alderley Park
- Age at study initiation: no data
- Weight at study initiation: mean 200g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data - Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: Not applicable, vapour
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 7 hours per day, 5 days per week
- Remarks:
- Doses / Concentrations:
700 mg/m3
Basis:
nominal conc. - No. of animals per sex per dose:
- 4
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Daily
FOOD CONSUMPTION: - No data
FOOD EFFICIENCY:- No data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
CLINICAL CHEMISTRY: No data
URINALYSIS: Yes
- Time schedule for collection of urine: Overnight after last exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - 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):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- 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:
- not examined
- Dose descriptor:
- NOEC
- Effect level:
- 700 mg/m³ air
- Sex:
- female
- Basis for effect level:
- other: overall effects no adverse effects
- Critical effects observed:
- not specified
- Conclusions:
- Methyl salicylate showed no evidence of toxicity by inhalation when tested at an effectively saturated concentration for 7 hours per day for four wekks.
- Executive summary:
4 female Alderley Park rats weighing an average of 200 g were exposed to a dynamic atmosphere (atmosphere continuously generated and passed through the exposure chamber) containing a saturated atmosphere (700 mg/m3) of methyl salicylate for 7 hours per day, 5 days per week for 4 weeks. Food and water were available ad libitum. Animals were weighed each day, and their condition and behaviour were recorded throughout the exposure period. Urine was collected overnight after the last exposure day for biochemical testing. Gross necropsy was conducted as well as microscopic examination of organs. Methyl salicylate at 700 mg/m3 (120 ppm), the maximum achievable atmosphere, did not cause any adverse effects (Gage, 1970).
Reference
No toxic signs and no macroscopic or microscopic effects were seen at necropsy following exposure to a saturated atmosphere for 7 hours per day, 5 days per week for 4 weeks.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 700 mg/m³
- Study duration:
- subacute
- Experimental exposure time per week (hours/week):
- 35
- Species:
- rat
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Single concentration tested. No data on substance purity.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- GLP compliance:
- no
- Species:
- rat
- Strain:
- other: Alderley Park
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Alderley Park
- Age at study initiation: no data
- Weight at study initiation: mean 200g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data - Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: Not applicable, vapour
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 7 hours per day, 5 days per week
- Remarks:
- Doses / Concentrations:
700 mg/m3
Basis:
nominal conc. - No. of animals per sex per dose:
- 4
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Daily
FOOD CONSUMPTION: - No data
FOOD EFFICIENCY:- No data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
CLINICAL CHEMISTRY: No data
URINALYSIS: Yes
- Time schedule for collection of urine: Overnight after last exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - 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):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- 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:
- not examined
- Dose descriptor:
- NOEC
- Effect level:
- 700 mg/m³ air
- Sex:
- female
- Basis for effect level:
- other: overall effects no adverse effects
- Critical effects observed:
- not specified
- Conclusions:
- Methyl salicylate showed no evidence of toxicity by inhalation when tested at an effectively saturated concentration for 7 hours per day for four wekks.
- Executive summary:
4 female Alderley Park rats weighing an average of 200 g were exposed to a dynamic atmosphere (atmosphere continuously generated and passed through the exposure chamber) containing a saturated atmosphere (700 mg/m3) of methyl salicylate for 7 hours per day, 5 days per week for 4 weeks. Food and water were available ad libitum. Animals were weighed each day, and their condition and behaviour were recorded throughout the exposure period. Urine was collected overnight after the last exposure day for biochemical testing. Gross necropsy was conducted as well as microscopic examination of organs. Methyl salicylate at 700 mg/m3 (120 ppm), the maximum achievable atmosphere, did not cause any adverse effects (Gage, 1970).
Reference
No toxic signs and no macroscopic or microscopic effects were seen at necropsy following exposure to a saturated atmosphere for 7 hours per day, 5 days per week for 4 weeks.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subacute
- Species:
- rat
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
Chronic toxicity studies:
Chronic toxicity studies have been conducted on MeS in rats and in dogs for two years (Webb and Hansen, 1963). Although the studies are relatively old and limited in endpoints evaluated, the protocol and results were reported in adequate detail and included haematological studies (reliability: 2)
Webb and Hansen (1963) administered methyl salicylate in the diet to groups of male and female Osborne-Mendel rats at concentrations of 0, 0.1%, 0.5%, 1.0% or 2.0% in the diet providing doses of approximately 0, 50, 250, 500, and 1000 mg/kg bw/day for two years. All rats in the 1000 mg/kg group died by the 49th week. Body weight of both sexes was significantly decreased in the 500 and 1000 mg/kg body weight/day groups. An increased amount of cancellous bone was present in the metaphyses in rats treated at either 500 or 1000 mg/kg body weight/day, with a more marked effect at the highest dose level. The relative testis weight of males was significantly increased as were the relative weights of the heart and kidneys of females in the 500 mg/kg body weight/day group. Gross pituitary gland lesions were found in 10 rats at 250 mg/kg bw/day compared to 4 animals in the control groups. Based on this study, the NOAEL is 50 mg/kg body weight/day. This NOAEL is obtained from 28 days to 2 years study and can be due to a constant hydrolysis rate.
The same authors fed MeS in capsule form to beagle dogs at doses of 0, 50, 150, or 350 mg/kg body weight/day, 6 days/week for 2 years. One high-dose animal died of hepatitis apparently unrelated to methyl salicylate. Hematological analyses at 1, 3, 6, 12 and 24 months and complete necropsy examination were normal, except that dogs treated at 150 and 350 mg/kg body weight/day had enlarged livers, seen microscopically as enlarged hepatic cells. No other pathology was reported in any of the animals. Reduced body weight was reported in the 350 and 150 mg/kg body weight/day groups. Based on this chronic oral study, the NOAEL is 50 mg/kg body weight/day.
NB:
Retrospective studies of children receiving salicylate therapy in the management of juvenile rheumatoid arthritis did not uncover any cases in which bone lesions or hepatomegaly (as seen in rats and dogs respectively) could be associated with massive daily doses of salicylate over prolonged periods of time. The reviews of human case histories (secondary reference, Abbott and Harrisson, 1978) suggest that the salicylate that the salicylate produced bone lesion in rats and hepatomegaly in dogs are not relevant to humans.
Subchronic toxicity studies:
1) Oral
Subchronic toxicity oral studies have been conducted on MeS in rats and dogs.
Rats:
In a 17 -week study in Osborn-Mendel rats (Webb & Hansen, 1963), male and female Osborne-Mendel rats were fed MeS 0%, 0.1% or 1.0% (0, 50 and 500 mg/kg bw/day) in the diet for 17 weeks. The high dose was associated with reduced bodyweight gain but had no effect on organ weight or histopathology. No effects were reported in the other dose groups. The results of this study support a NOAEL value of 0.1% in the diet, equivalent to 50 mg/kg bw/day.
A set of six studies of 6 to12 week duration examined the effects of MeS on bone metabolism and growth (Abbott & Harrisson, 1978) in SD rats fed a diet containing 0.2%, 0.36%, 0.63%, 1.13%, or 2.0% (equivalent to 100, 180, 320, 560 and 1000 mg/kg/day ) MeS. Bone lesions and growth retardation were observed in rats fed MeS at 1% and 2% in diet. These studies indicated a NOAEL of 180 mg/kg/bw/day.
Dogs:
In a subchronic study (Webb and Hansen, 1963), groups of two beagle dogs, one male and one female, were given 50 to 1200 mg/kg of MeS orally in capsule form daily 6 days per week for up to 59 days. All dogs receiving 500 mg/kg/day or more lost weight and died or were killed due to moribund condition within 1- month of study initiation. Moderate to marked fatty changes were observed in the liver of one animal at 800 mg/kg and both at 1200 mg/kg. Animals given 500 mg/kg had diarrhea and weakness during their last 3 days. No adverse effects were observed in animals given 50, 150 and 250 mg/kg/day MeS. A NOAEL of 250 mg/kg bw/day was identified.
In the second of two studies (Abbott & Harrisson, 1978) MeS was administered via capsule at 50, 100 or 167 mg/kg/day, 6 days/week, to groups of male and female beagles for 6 months. Two high-dose and control dogs of each sex were allowed a 2 -month recovery period. There were no treatment-related effects on body weight, liver or kidney weights, or on the results of hematological and clinical chemistry evaluations. The NOAEL was 167 mg/kg/day, the highest dose tested.
2) Dermal
Webb and Hansen (1963), applied MeS dermally to groups of three rabbits of mixed sex at 0.5, 1.0, 2.0 and 5.0 mL/kg (590, 1180, 2360, and 4720 mg/kg) body weight/day, 5 days per week for up to 96 days. All 3 high-dose animals had died by day 28 of exposure, following weight loss and depressed activity. In one of these animals, local effects on the skin and lesions in a number of organs were reported. The only effect reported in the other high dose animal examined was a suggestion of an effect on the distal portion of nephrons. At 2.0 ml/kg (2360 mg/kg), slight sloughing of epidermal scales was observed in 2/3 rabbits. No dermal effects were noted in rabbits exposed to 0.5 or 1.0 ml/kg (590 and 1180 mg/kg body weight/day). The NOAEL for local effects was 1.0 ml/kg/day (1180 mg/kg bw/day). No clear NOAEL was determined for systemic effects due to the reported increased incidence in spontaneous nephritis and mild hepatitis over that in rabbits in other experiments. This dermal study at very high doses was limited in design and in reporting detail and is not useful for risk assessment for systemic toxicity.. It is not possible to determine whether the effects reported on kidney and other organs in one high dose animal represent systemic toxicity or a secondary effect due to skin and muscle damage.
Subacute toxicity studies
Inhalation
4 femalerats were exposed to a saturated atmosphere (700 mg/m3) of MeS for 7 hours per day, 5 days per week for 4 weeks. Animals were weighed each day, and their condition and behaviour were recorded throughout the exposure period. Urine was collected overnight after the last exposure day for biochemical testing. Gross necropsy and microscopic examination of organs was carried out. MeS at 700 mg/m3 (120 ppm), the maximum achievable atmosphere, did not cause any adverse effects (Gage, 1970).
Conclusion:
From the chronic studies in rats and dogs, a systemic NOAEL of 50 mg/kg bw/day can be used for quantitative human health risk assessment of the use of MeS. The target organ being bone, not seen in children (secondary reference, Abbott and Harrisson, 1978.).
Repeated dose toxicity: via oral route - systemic effects (target organ) other: bone
Justification for classification or non-classification
The guidance values for classification of a substance as harmful on repeated exposure by the oral route according to the criteria of Annex VI Directive 67/748/(R48/22) relate to severe effects reported at 50 mg/kg bw/day or below in a 90-day study. The equivalent guidance values for classification according to EU/GHS criteria (STOT Category 2) relate to effects reported at 10-100 mg/kg bw/day in a 90-day study.
For MeS, the no-effect level in both 17-week and 2-year oral dietary studies (Webb & Hansen, 1963) was 50 mg/kg bw/day. Slight effects on bone density were reported at the LOAEL of 500 mg/kg bw/day in the subchronic study.
MeS is not classified for repeat-dose toxicity according to the criteria of Annex VI Directive 67/748/EECor UN/EU GHS.
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