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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

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
50 mg/kg bw/day
Study duration:

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
700 mg/m³
Study duration:

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.


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.


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.


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


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).


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.