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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
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: 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.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Chronic and subacute toxicology and pathology of methyl salicylate in dogs, rats and rabbits
Author:
Webb WK, Hansen WH
Year:
1963
Bibliographic source:
Toxicology and Applied Pharmacology 5: 576-687

Materials and methods

Test guideline
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: methyl salicylate
- Molecular formula: C8H8O3
- Substance type: oily liquid
- Physical state: it was colorless, had a specific gravity of 1.17 and had the odor of wintergreen
- Analytical purity: 99%
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals 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

Administration / exposure

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 a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 150 and 350 mg/kg/day
Basis:
no data
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

Examinations

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 are available

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):
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.

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see below

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

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.
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.