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EC number: 204-317-7
CAS number: 119-36-8
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).
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:
Subchronic toxicity oral studies have been conducted on MeS in rats and
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
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.
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
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
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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