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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
no data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: This study is limited in design and in reporting detail. Few animals were used, at very high dose levels
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:
Toxicol Appl Pharmacol 5: 576-687

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Rabbits were treated on their backs with four dose levels of methyl salicylate for approximately 6.5 hours daily for up to 96 days. Since the compound was absorbed, the backs of the rabbits were not wiped before they were replaced in their individual cages. Microscopic examinations were made of the major organs
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: methyl salicylate
- Substance type: oily liquid
- Physical state: colorless, had a specific gravity of 1.17, and had the odor of wintergreen
- Analytical purity: 99%

Test animals

Species:
rabbit
Strain:
not specified
Sex:
male/female

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
up to 96 days
Frequency of treatment:
daily on five days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5, 1.0, 2.0 and 4.0 ml/kg/day (590, 1180, 2360, and 4720 mg/kg body weight/day)
Basis:
nominal per unit body weight
No. of animals per sex per dose:
3 per dose level (mixed sexes)
Control animals:
no

Examinations

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Local dermal effects

Results and discussion

Results of examinations

Dermal irritation:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
The three rabbits on 4.0 ml/kg died after 6, 8, and 28 days and exhibited anorexia, weight loss, and depression.

BODY WEIGHT AND WEIGHT GAIN
Several of the survivors had subnormal weight gains

HISTOPATHOLOGY:
Microscopically: one high-dose animal had "several distinct lesions" including dilatation, desquamation, and formation of new atypical epithelium of the renal tubules; a moderate number of small foci of superficial necrosis and sloughing of the skin; foci of moderate necrosis and slight calcification of voluntary muscles; marked vacuolation of pancreatic acinar cells, slight myeloid hyperplasia and shift to the left of bone marrow, and slight hepatitis. These effects were not seen in the other examined high-dose animals, but an effect on the distal portion of the nephrons was indicated.The incidence of spontaneous nephritis and mild hepatitis in the nine surviving rabbits was increased over that in rabbits in other experiments.
OTHER FINDINGS: A slight sloughing of epidermal scales occurred in two of the three rabbits on 2.0 ml/kg/day. The remaining animals showed no skin abnormalities.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
Local effects
Effect level:
1 180 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: slight to very slight dermatitis (sloughing of epidermal scales) at 2.0 ml/kg bw/day (2360 mg/kg bw/day)
Dose descriptor:
LOAEL
Remarks:
Systemic effects
Effect level:
590 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Increased spontaneous nephritis and mild hepatitis.
Dose descriptor:
LOAEL
Remarks:
Systemic effects
Effect level:
974 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: read-across value for 2-ethylhexyl salicylate

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

One high dose decedent was not necropsied due to extreme autolysis. Of the two high dose animals examined, one showed local dermal effects (small foci of superficial necrosis and sloughing of the skin) as well as lesions in several organs (kidney, voluntary muscle, pancreas, bone marrow, liver). 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.

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the NOAEL value for local dermal effects of methyl salicylate was 1.0 ml/kg/day (1180 mg/kg bw/day). The LOAEL for systemic effects was 0.5 ml/kg/day (590 mg/kg bw/day) for methyl salicylate, which corresponds to 974 mg/kg bw/day of 2-ethylhexyl salicylate.
Executive summary:

In a study by Webb and Hansen (1963), groups of three rabbits of both sexes were administered methyl salicylate of 99% purity to sites on the back clipped free of hair. Dermal exposures of 0.5, 1.0, 2.0 and 4.0 ml/kg/day (590, 1180, 2360, and 4720 mg/kg body weight/day) were administered 5 days/week for up to 96 days. The animals were restrained in holders for 6.5 h, but due to absorption the test substance was not wiped from the test sites after the exposure period. Following termination, the major organs from all rabbits except one severely autolysed animal were subjected to histological examination.

All the 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 (small foci of superficial necrosis and sloughing of the skin) and lesions in a number of organs (skin, kidney, voluntary muscle, pancreas, bone marrow, liver) 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), however the lower pH of SA predicts a higher potential for irritation for the acid than for the ester. No clear NOAEL for local effects for SA could therefore be determined.

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 the purposes of 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.