Reaction mass of isopentyl salicylate and 2-methylbutyl salicylate

Toxicity to reproduction

Administrative data

Endpoint:

three-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Effect of Methyl Salicylate on Rat Reproduction

Author:

T. F. X. COLLINS, W. H. HANSEN, AND H. V. KEELER

Year:

1969

Bibliographic source:

Bureau of Foods and Pesticides, Food and Drug Administration, U.S. Department of Health, Education, and Welfare, Washington, D.C. 20204

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: three-generation reproductive toxicity

Principles of method if other than guideline:

Principles included in the following reference: FITZHUGH, 0. G. (1968). Modern Trends in Toxicology, I (E. Boyland and R. Goulding, eds.), pp. 75-85. Butterworth, London.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methyl salicylate

EC Number:

204-317-7

EC Name:

Methyl salicylate

Cas Number:

119-36-8

Molecular formula:

C8H8O3

IUPAC Name:

methyl salicylate

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): Methyl salicylate
- Molecular formula (if other than submission substance): C8H8O3
- Molecular weight (if other than submission substance): 152.14 g/mol
- Smiles notation (if other than submission substance):
- Physical state: colourless, oily liquid
- Analytical purity: 99%
- Impurities (identity and concentrations): not reported
- Composition of test material, percentage of components: not reported
- Purity test date: not reported
- Lot/batch No.: not reported
- Expiration date of the lot/batch: not reported

Specific details on test material used for the study:

Synthetic methyl salicylate* was mixed with Purina Laboratory Chow at concentrations of 0, 500, 1500, 3000, and 5000 ppm and fed ad libitum. The diet was prepared every 14 days in a manner identical to that of Webb and Hansen (1963) and according to the results of Jones et al, (1962).

Test animals

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Duration of treatment / exposure:

100 days

Frequency of treatment:

Once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

25 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

75 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

150 mg/kg bw/day (nominal)

Doses / concentrations 5

Dose / conc.:

250 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20 males and 20 females in each dose group

Control animals:

not specified

Examinations

Litter observations:

At the birth of the first litter (F,,) observations were made of the number of stillborn and liveborn young and of grossly visible abnormalities. Litters were similarly observed on day 4 and counts were made of the number and conditions of the living pups. When litters exceeded 10 at day 4, the number of pups was reduced to 10. At weaning the animals were sacrificed.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 75 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

body weight and weight gain

Results: F1 generation

General toxicity (F1)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Significant decreases in average litter size were found in the second generation in the second mating at 3000 ppm (P K 0.05) and in both matings at 5000 ppm. Although decreases were seen at 1500 ppm, they were not statistically significant because of the large variation in progeny between females within a group. A dose-related decrease in average litter size per female exposed was apparent in both matings of the second generation starting at 1500 ppm. When the results were combined for all generations, mating 1 and mating 2, there was a clearly dose-related decrease starting at 1500 ppm.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

75 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Results: F2 generation

General toxicity (F2)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Significant decreases in average litter size were found in the second generation in the second mating at 3000 ppm (P K 0.05) and in both matings at 5000 ppm. Although decreases were seen at 1500 ppm, they were not statistically significant because of the large variation in progeny between females within a group. A dose-related decrease in average litter size per female exposed was apparent in both matings of the second generation starting at 1500 ppm. When the results were combined for all generations, mating 1 and mating 2, there was a clearly dose-related decrease starting at 1500 ppm.

Effect levels (F2)

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

ca. 75 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

body weight and weight gain

Overall reproductive toxicity

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

150 mg/kg bw/day (nominal)

Treatment related:

yes

Relation to other toxic effects:

not specified

Dose response relationship:

yes

Applicant's summary and conclusion

Conclusions:

Adverse effects were seen at the 3000 and 5000 ppm dose levels (150 and 250 mg/kg), particularly in second generation matings which showed consistent, statistically significant decreases for average litter size, average number of liveborn, and average numbers of survivors to day 4 and day 21. Although no statistically significant decreases were shown in any generation at the 500 or 1500 ppm dose levels (25 and 75 mg/kg) of methyl salicylate fed alone, there were decreases in the number of progeny born per female exposed to mating. These decreases were not significant because of the large variation in number of progeny between females within a group. The decreases, although not statistically significant, indicate possible adverse biological effects.

Executive summary:

The flavoring agent methyl salicylate was fed at 0, 500, 1500, 3000, and 5000 ppm to Osborne-Mendelr ats for 3 generations,No significant decrease was seen in

the fertility index at any dose.A t the 3000-a nd 5000-ppm levels significant decreases were seen in average litter size, average number of livebom progeny, average number of survivors to day 4, and average number of survivors to weaning.T he decreasews ereg reatesti n the secondg eneration. The decreases eenin the number of liveborn progeny appeared o be dose-related.