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EC number: 204-263-4 | CAS number: 118-60-5
- 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
NOAEL (oral, dog, 2 year chronic): 83 mg/kg bw/d 2-ethylhexyl salicylate adjusted
NOEAC (inhalative, rat, 28d subacute): 1155 mg/m³ 2-ethylhexyl salicylate adjusted
Key value for chemical safety assessment
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:
- weight of evidence
- Study period:
- no data
- 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 administered in dogs orally in capsule daily for a period of 2 years.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
IN-LIFE DATES: no data - Route of administration:
- oral: capsule
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
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: none - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- none
- Duration of treatment / exposure:
- 2 years
- Frequency of treatment:
- daily for 6 days/week
- Remarks:
- Doses / Concentrations:
0, 50, 150 and 350 mg/kg/day
Basis:
actual ingested - No. of animals per sex per dose:
- 2/sex/dose
- Control animals:
- yes
- Details on study design:
- no data are available
- Dose selection rationale: the data reported in the subchronic study in dogs by the same authors (methyl salicylate/ 59 days/oral (capsule)/dogs). - Positive control:
- none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: the animals were weighed weekly
FOOD EFFICIENCY: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY:
it made at 2 weeks, 1, 3, and 6 months and 1 and 2 years
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- no data
- Statistics:
- no data available
- 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
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- 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:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- No clinical signs were observed.
- Two dogs dying of unrelated disease: one high-dose female died of infectious canine hepatitis after 33 days on the experiment.
Her replacement died of canine distemper after 19 weeks on the experiment.
BODY WEIGHT AND WEIGHT GAIN
The administration of 350 and 150 mg/kg/day retarded the growth of the dogs:
- The dogs on the highest level lost an average of 1.90 kg while the control dogs gained an average of 1.85 kg.
- The dogs on 150 mg/kg/day gained an average of only 0.5 kg.
HAEMATOLOGY
Hematological analyses at 1, 3, 6, 12 and 24 months were normal.
ORGAN WEIGHTS
Enlarged livers were seen at necropsy of the dogs on the 150 and 350 mg/kg/day levels. The heavier livers plus reduced bodyweight gain produced higher ratios of liver weight to body weight.
GROSS PATHOLOGY
At necropsy, the dogs treated at 150 and 350 mg/kg body weight/day had enlarged livers.
HISTOPATHOLOGY:
Microscopically, these livers had larger hepatic cells than those seen in the control dogs.
Fatty metamorphosis was not greater in the livers of the treated dogs than the very small amounts seen in the livers of the control dogs. - Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: for methyl salicylate
- Dose descriptor:
- NOAEL
- Effect level:
- 83 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: read-across value for 2-ethylhexyl salicylate
- Critical effects observed:
- not specified
- Conclusions:
- Under these test conditions, animals of the 150 and 350 mg/kg groups had retarded growth and enlarged livers were observed in these animals. No effects were reported at 50 mg/kg bw/day. Based on this study, the NOAEL /oral/dogs is 50 mg/kg body weight/day for methyl salicylate. This corresponds to 83 mg/kg bw/day of 2-ethylhexyl salicylate.
- Executive summary:
Webb and Hansen (1963) studied groups of two male and two female purebred beagles fed methyl salicylate in capsule form 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 value is 50 mg/kg body weight/day.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 83 mg/kg bw/day
- Study duration:
- chronic
- Species:
- dog
- Quality of whole database:
- The findings of three weight of evidence studies (subchronic in rat with 2-ethylhexyl salicylate, chronic in rats and dogs with methyl salicylate as read -across substance) are supported by a subacute study according to OECD 421 which also investigated 2-ethylhexylsalicylate and two further subchronic studies with rats and dogs tested with methyl salicylate.
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
- Details on study design:
- not given
- Positive control:
- no data
- 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 - Other examinations:
- none
- Statistics:
- no data
- 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:
- NOAEC
- Effect level:
- 700 mg/m³ air (nominal)
- Basis for effect level:
- other: overall effects, no adverse effects. Values for methyl salicylate.
- Dose descriptor:
- NOAEC
- Effect level:
- 1 155 mg/L air (nominal)
- Basis for effect level:
- other: read-across value for 2-ethylhexyl salicylate
- 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 weeks. The highest tested concentration of methyl salicylate of 700 mg/m³ corresponds to 1155 mg/m³ of 2-ethylhexyl salicylate.
- 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
- 1 155 mg/m³
- Study duration:
- subacute
- 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
- Details on study design:
- not given
- Positive control:
- no data
- 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 - Other examinations:
- none
- Statistics:
- no data
- 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:
- NOAEC
- Effect level:
- 700 mg/m³ air (nominal)
- Basis for effect level:
- other: overall effects, no adverse effects. Values for methyl salicylate.
- Dose descriptor:
- NOAEC
- Effect level:
- 1 155 mg/L air (nominal)
- Basis for effect level:
- other: read-across value for 2-ethylhexyl salicylate
- 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 weeks. The highest tested concentration of methyl salicylate of 700 mg/m³ corresponds to 1155 mg/m³ of 2-ethylhexyl salicylate.
- 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
- 1 155 mg/m³
- 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
Repeat dose data for oral, inhalative and dermal exposure are available on methyl salicylate as surrogate substance for 2-ethylhexyl salicylate and oral data on 2-ethylhexyl salicylate. Whereas chronic studies on methyl salicylate using rats and dogs are considered reliable and the subacute inhalative study using methyl salicylate is considered reliable too, the dermal study applying methyl salicylate to rats falls short due to a low number of animals used and high doses applied. Therefore, the dermal study with methyl salicylate was not considered reliable. The findings in the oral chronic studies with methyl salicylate in rats and dogs are well in line with those in a 90-day chronic repeat dose toxicity study with and a subacute study on 2-ethylhexyl salicylate and thus are used as key studies in a weight of evidence approach.
A read-across justification is provided as attachment to IUCLID section 13 respectively as appendix to the CSR.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
compliant chronic study for read-across substance methyl salicylate as worst case result supported by studies on methyl salicylate and 2-ethylhexyl salicylate, all considered reliable.
Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
One study available on read-across substance methyl salicylate
Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
One study available on read-across substance methyl salicylate
Justification for classification or non-classification
Based on weight of evidence using the 90-day oral feeding study with 2-ethylhexyl salicylate, supported by the results of a OECD 421 study, and the chronic data on methyl salicylate sharing the same primary metabolite (salicylic acid) with the target substance the NOAEL for this substance is set to 83 mg/kg bw/d based on chronic data in a study with beagle dogs. At this dose no relevant toxic effect were observed. Thus a classification for Specific target Organ Toxicity - Repeated Exposure (STOT RE) according to CLP (Regulation EC No 1272/2008) is not required. Also, according to DSD (Directive 67/548/EEC) a classification for chronic toxicity (R 48) is not required.
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