Methyl salicylate

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Remarks:

unpublished report cited by FDA and RAC (ANSES has access to the original studies cited in the FDA report, and considers this study as the Key study with a Klimisch reliability of 1)

Data source

Reference

Reference 1

Reference Type:

publication

Title:

RAC Opinion proposing harmonised classification and labelling at EU level of Methyl salicylate (EC Number: 204-317-7; CAS Number: 119-36-8)

Author:

ECHA, Committee for Risk Assessment

Year:

2019

Bibliographic source:

RAC Opinion. Methyl salicylate (EC Number: 204-317-7; CAS Number: 119-36-8). CLH-O-0000006716-67-01/F. Adopted 20 September 2019. https://echa.europa.eu/registry-of-clh-intentions-until-outcome/-/dislist/details/0b0236e182310e47

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

2006

Materials and methods

Principles of method if other than guideline:

Males were dosed daily 2 weeks prior to mating, throughout mating period and up to one day prior to euthanasia ((total of 52 days). Females were dosed daily 2 weeks prior to mating, throughout mating period and up to Gestation Day 6 (total of 30 days). Sacrifice of females on GD13.

GLP compliance:

yes

Limit test:

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

Details on test material:

Lot Y096

Test animals

Species:

rat

Strain:

other: Crj:CD(SD)IGS rats

Sex:

male/female

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

corn oil

Details on exposure:

dose volume of 1 mL/kg

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

30 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

0 mg/kg bw/day (nominal)

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during the dosing period and once daily the other periods

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: males BW were recorded twice weekly throughout the dosing period until euthanasia. Female BW were measured twice weekly from the start of the mating and daily during gestation.

FOOD CONSUMPTION : male's food consumption was recorded twice weekly throughout the dosing period until euthanasia. Female's food consumption was measured twice weekly from the start of dosing to the start of mating and daily during gestation.

WATER CONSUMPTION AND COMPOUND INTAKE: No data

Oestrous cyclicity (parental animals):

Vaginal smears for determining the stage of estrous were evaluated daily from the start of administration and continued until evidence of copulation was observed.

Sperm parameters (parental animals):

sperm mobility and morphology were analysed.

Postmortem examinations (parental animals):

GROSS NECROPSY
- Gross necropsy consisted of examination of the organs and tissues.

HISTOPATHOLOGY / ORGAN WEIGHTS
The testes, left epididymis, ovaries and skin of the treated site were preserved for histological examination. Also organs with lesions were preserved for histological examination.
Weights of the following organs were obtained: testes, epididimis.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

One male at 300 mg/kg/day showed hypoactivity, bradypnea, hypothermia and blanching on day 3 and died on day 4. Crust on the treated site and/or loss of hair were observed in 2 females at 300 mg/kg/day from day 9 of administration to day 13 of gestation. A significant lower body weight, body weight gain and food consumption was observed in males and females at the highest dose. There was no significant difference in the weights of the testes or epididymides. There was no significant difference in the count of oestus or estrous cycle. The copulation indices were 100, 100, 95.00, 94.74% for each group, respectively. The male and female fertility indices were 100, 90.00, 94.74, 94.44% for control, 30, 100 and 300 mg/kg/day respectively. There was no significant difference between control and methyl salicylate groups in the sperm form anomalies index, sperm count or sperm motility. There was no significant difference in the numbers of implants or live embryos, pre-implant low index or dead embryo index. A significant decrease in the number of corporea lutea was observed at 100 mg/kg/day (1.84% versus 4.81% in control) but not at 300 mg/kg/day (3.25%). Plasma salicylic acid concentration was measured on day 0 and day 13 of administration. The increase was nearly dependent on increases in the dose ratio and was scarcely affected by repeated dosing. No sexual difference was observed.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

2

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

Remarks on result:

other: no effect observed on fertility

Results: F1 generation

Effect levels (F1)

Remarks on result:

not measured/tested

Overall reproductive toxicity

Reproductive effects observed:

no

Applicant's summary and conclusion

Executive summary:

In a study summarized in FDA (2006) and RAC opinion (2019), 20/sex rats were exposed subcutaneously to methyl salicylate (MeS) at 0, 30, 100 or 300 mg/kg/day 2 weeks prior to mating until sacrifice of males and until gestation day 6 for females. Females were sacrificed on gestation day 13. One male at 300 mg/kg/day showed hypoactivity, bradypnea, hypothermia and blanching on day 3 and died on day 4. Crust on the treated site and/or loss of hair were observed in 2 females at 300 mg/kg/day from day 9 of administration to day 13 of gestation. A significant lower body weight, body weight gain and food consumption was observed in males and females at the highest dose. There was no significant difference in the weights of the testes or epididymides. There was no significant difference in the count of oestus or estrous cycle. The copulation indices were 100, 100, 95.00, 94.74% for each group, respectively. The male and female fertility indices were 100, 90.00, 94.74, 94.44% for control, 30, 100 and 300 mg/kg/day respectively. There was no significant difference between control and methyl salicylate groups in the sperm form anomalies index, sperm count or sperm motility. There was no significant difference in the numbers of implants or live embryos, pre-implant low index or dead embryo index. A significant decrease in the number of corporea lutea was observed at 100 mg/kg/day (1.84% versus 4.81% in control) but not at 300 mg/kg/day (3.25%). Plasma salicylic acid concentration was measured on day 0 and day 13 of administration. The increase was nearly dependent on increases in the dose ratio and was scarcely affected by repeated dosing. No sexual difference was observed. In conclusion, the NOAEL for general toxicity is 100 mg/kg/day and the NOAEL for fertility and early development was 300 mg/kg/day.