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Toxicological information

Carcinogenicity

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Description of key information

Based on negative genotoxicity data derived for this substance and supportive information from a 2-year carcinogenicity study with methyl salicylate, carcinogenic properties are not expected.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: It is an old study (1963); no GLP. 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:
reference to same study
Qualifier:
no guideline available
Principles of method if other than guideline:
2-year feeding study in rats
GLP compliance:
no
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals 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 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
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Post exposure period:
none
Remarks:
Doses / Concentrations:
0, 0.1, 0.5, 1 and 2%
Basis:
nominal in diet
equivalent to 0, 50, 250, 500, and 1000 mg/kg bw/day
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
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
Statistics:
not reported
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 examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
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
Description (incidence and severity):
pituitay lesions
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
pituitary lesions
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
no significant increase in any neoplasm
Details on results:
CLINICAL SIGNS AND MORTALITY
Animals of the 1.0% and 2.0% groups developed rough hair coats.
In the high-dose (2.0%) 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 WEIGHTS: Average 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. Incidence in the 1.0% group was similar to controls. Animals of the 2.0% group died before the age at which spontaneous lesions develop.
In the 2% group, 29 of the 50 animals had pneumonia, which appeared to be more acute than regularly observed.
Other gross lesions were seen in similar numbers of rats on all diets.

HISTOPATHOLOGY: NON-NEOPLASTIC
See chronic study.

HISTOPATHOLOGY: NEOPLASTIC
Benign pituitary tumors occurred in similar numbers of surviving rats on all diets, with incidence higher in females than males.
Malignant pituitary tumors occurred in 1 male and 2 female rats on the 0.5% diet, but not the 1.0% diet.
Mammary tumors occurred in females rats on all diets.
Relevance of carcinogenic effects / potential:
Incidence of tumours in rats exposed to methyl salicylate in the diet was not increased over controls. As discussed in the ECHA dissiminated REACH dossier on methyl salicylate, this study and data on other salicylates suggest that salicylic acid and its esters have no carcinogenic potential.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: for methyl salicylate
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
860 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Read-across value for homosalate.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Conclusions:
Methyl salicylate is not carcinogenic in this test system.
Executive summary:

Webb and Hansen (1963) administered methyl salicylate in the diet to groups of 24-25 male and 25-26 female Osborne-Mendel rats at dietary concentrations of 0, 0.1%, 0.5%, 1.0% or 2.0%, providing doses of approximately 0, 50, 250, 500, and 1000 mg/kg body weight/day for two years. All rats in the 1000 mg/kg group died by the 49th week. Body weight of both sexes were significantly decreased in both the 500 and 1000 mg/kg group body weight/day groups.

Gross pituitary gland lesions were found in 10 rats at 250 mg/kg bw/day compared to 4 rats in the control groups. Incidence in the 500 mg/kg/day group was similar to controls, while all animals of the 1000 mg/kg/day group died before the usual age at which many spontaneous lesions develop.

Similar kinds and numbers of tumors occurred in rats of all diets except the 1000 mg/kg/day group (premature decedents), with mammary tumors of the females being the most common. Benign pituitary tumors occurred in similar numbers of surviving rats on all diets, with occurrence predominantly in females. Malignant pituitary tumors occurred in one male and two females receiving 250 mg/kg/day. Since no such tumors were reported in either the lower or higher dose groups (50 and 500 mg/kg/day), this low incidence does not clearly indicate any relation with methyl salicylate treatment.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No study on carcinogenicity is available for homosalate but a supportive study with the read-across substance methyl salicylate was negative for carcinogenicity. Based on negative genotoxicity data derived for homosalate and supportive information from a 2-year carcinogenicity study with methyl salicylate, carcinogenic properties are not expected and no further studies are proposed.


Justification for selection of carcinogenicity via oral route endpoint:
No study on carcinogenicity is available for homosalate but a supportive study with the read-across substance methyl salicylate was negative for carcinogenicity.

Justification for classification or non-classification

Based on negative genotoxicity data derived for this substance and supportive information from a 2-year carcinogenicity study with methyl salicylate as read-across substance, carcinogenic properties are not expected and thus the substance is not classified for carcinogenicity according to CLP (Regulation EC No 1272/2008) or DSD (Directive 67/548/EEC).