Salicylic acid

Carcinogenicity

Description of key information

Assessment of the carcinogenic potential of SA has been made based on one screening carcinogenicity study on SA itself, plus data on carcinogenic potential of methyl salicylate (MeS), sodium salicylate (NaS) and Acetylsalicylic acid (ASA).

No relevant Human information is available on SA but Human use of ASA indicate in many cases cancer prevention (see ASA dossier)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key 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 for cross-reference:

reference to same study

Principles of method if other than guideline:

Method: other

GLP compliance:

no

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system 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

Dose / conc.:

0.1 other: %

Remarks:

equivalent to 50 mg/kg bw/day; Basis: nominal in diet

Dose / conc.:

0.5 other: %

Remarks:

equivalent to 250 mg/kg bw/day; Basis: nominal in diet

Dose / conc.:

1 other: %

Remarks:

equivalent to 500 mg/kg bw/day; Basis: nominal in diet

Dose / conc.:

2 other: %

Remarks:

equivalent to 1000 mg/kg bw/day; Basis: nominal in diet

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

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

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.

Dose descriptor:

NOAEL

Remarks:

500 mg/kg bw/day

Sex:

male/female

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 250mg/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

Justification for classification or non-classification

Not carcinogenic according to EU and GHS (UN/EU) criteria.

Based on absence of carcinogenicity in a screening study on SA and in chronic toxicity studies on MeS in rats and dogs.

Additional information

No standard rodent carcinogenicity study using the current OECD protocol is available on salicylic acid.  Assessment of the carcinogenic potential of SA has therefore been made based on one screening carcinogenicity study on SA itself, plus data on carcinogenic potential of methyl salicylate (MeS), sodium salicylate (NaS) and Acetylsalicylic acid (ASA).  The initial step in the metabolism of all these salicylate compounds is hydrolysis to free salicylate.

In a screening test for carcinogenic hazard of SA (Uhmeda. 1957), rats were fed with salicylic acid or injected with sodium salicylate in solution. None of the animals treated with salicylic acid developed tumors in any organ in the course of the experiment. No marked change in internal organs was found in the rats treated with sodium salicylate under the conditions of this experiment.

The evaluation of the carcinogenic potential of MeS was included in 2 -year studies on the chronic toxicity of MeS by the oral route in rats and dogs (Webb and Hansen, 1963). In the rat, at 0, 0.1%, 0.5%, 1.0% or 2.0% MeS in diet, the only tumors described were pituitary tumours. Similar incidences of benign pituitary tumours were reported in controls and treated rats. Malignant pituitary tumours were reported in 3 rats at 0.5% but none at 1% MeS in diet. No tumors were reported in dogs fed MeS in capsule form at doses of 0, 50, 150 or 350 mg/kg/bw/day for 2 years.

In a non-standard carcinogenicity study (Stoner et al., 1973), MeS was tested by the intraperitoneal route in the A/He strain of mouse, a strain susceptible to carcinogen-induced lung tumorigenesis. In the low-dose group, 2/15 (13%) males and 1/15 (6%) females developed lung tumors while in the high-dose group, 1/15 males (6%) and 5/15 (33%) females developed lung tumors. In comparison, 22/80 (28%) male and 16/80 (20%) female control mice developed "spontaneous" lung tumors. MeS was reported as negative for pulmonary tumour response in this assay.

In Chang et al. (1983), the cocarcinogenic potential of acetylsalicylic acid on gastric tumors induced by N-Nitroso-N-methylnitroguanidine in rats was studied. No gastro-intestinal tumors were found with rats treated only with acetylsalicylic acid twice a week for 18 months.

MeS has been studied for anti-carcinogenic potential in several older assays (Strong, 1932 and Boyland and Huntsman-Mawson, 1938). A number of epidemiological studies have claimed that low doses of aspirin (ASA) are effective in preventing colorectal cancer.  The most detailed scientific evaluation on the efficacy of aspirin (ASA) as a colorectal cancer chemopreventive has been conducted by a Working Group of experts convened by the International Agency for Research on Cancer (IARC). This Working Group (IARC, 1997) considered that the strength of scientific evidence that aspirin prevents colorectal cancer in humans was limited.[p1] 

Taken together, the data on these salicylates suggest that salicylic acid would have no carcinogenic potential.

 [p1]IARC Handbooks of Cancer Prevention. Volume 1 - Non-steroidal anti-inflammatory drugs. International Agency for Research on Cancer, , 1997.

Justification for selection of carcinogenicity via oral route endpoint:
Full reliability 2 study