p-tolyl acetate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data from NTP study report.

Data source

Reference

Reference Type:

secondary source

Title:

Methyl Salicylate: Reproduction and Fertility Assessment in CD-l Mice When Administered by Gavage

Author:

Environmental Health Research and Testing, Inc

Year:

1984

Bibliographic source:

National Toxicology Program, Research Triangle Park, NC. NTP85-022 - PB85-l64283, 1984, page no 1- 165

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: According to Fertility Assessment by Continuous Breeding (FACB) protocol

Principles of method if other than guideline:

Reproduction and fertility assessment of methyl salicylate in CD-1 mice when administered by gavage.

GLP compliance:

not specified

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 2-hydroxybenzoate

Test material form:

other: Liquid

Details on test material:

- Name of test material (as cited in study report):Methyl Salicylate
- Molecular formula : C8H8O3
- Molecular weight : 152.14 g/mole
- Substance type: Oragnic
- Physical state:Liquid
- Impurities (identity and concentrations): < 1 %

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Fisher Scientific Co.
(Lot #703535)
- Expiration date of the lot/batch: No data
- Purity: >/= 99%

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory Inc. (Kingston, N.Y.).
- Age at study initiation: (P) x wks; (F1) x wks: F0: 11 weeks
F1: 70 ± 10 days
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: F0: male- 34.5 ± 0.58 to 35.6 ± 0.76g , Female: 26.3 ± 0.66 to 27.6 ± 0.60g
F1: male- 1.65 ± 0.014 to 1.60 ± 0.023g, female: 1.53 ± 0.016 to 1.60 ± 0.014g
- Fasting period before study: No data available
- Housing: Animals were housed 2 per Polycarbonate shoebox type cages (5" x 11" x 7") with stainless steel wire bar lids, one of these animals will be punched in the left ear for identification purposes. Cages will be uniformly placed on stainless steel racks (66" x 60" x 30"). Cages will be rotated (relative placement) at least once a week. Bedded on Ab-Sorb-Dri , Approximately 100g of bedding will be used per cage.
- Diet (e.g. ad libitum): Purina certified Rodent Chow animal diet #5002, ad libitum.
- Water (e.g. ad libitum): Water, ad libitum.
- Acclimation period: F0: 1 week , F1: five weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25° C
- Humidity (%):20 to 70%
- Air changes (per hr): 10 or more air changes per hour of HEPA-filtered air.
- Photoperiod (hrs dark / hrs light): 14 hour light cycle

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dosing solutions were formulated by mixing the test article directly into different proportions of corn oil.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food:No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 0.1, 0.25, and 0.5 g/kg
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): No data
- Purity:No data

Details on mating procedure:

- M/F ratio per cage:1: 1 ratio
- Length of cohabitation: 100 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: No data available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.: No data available
- Further matings after two unsuccessful attempts: No data available
- After successful mating each pregnant female was caged (how): Individually
- Any other deviations from standard protocol: Litters produced during the cohabitation period (day 7 to day 107) will be humanely sacrificed. Litters produced during the period day 107 to day 127 will be allowed to remain with their mothers

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

127 days

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.1, 0.25 and 0.50 g/kg (0, 100, 250 and 500 mg/kg/day)
Basis:
no data

No. of animals per sex per dose:

Total: 200
0 mg/kg/day: 40 male, 40 female
100 mg/kg/day: 20 male, 20 female
250 mg/kg/day: 20 male, 20 female
500 mg/kg/day: 20 male, 20 female

Control animals:

yes, concurrent vehicle

Positive control:

No data avaialble

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS:No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations:No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OTHER: Mortality: Yes

Oestrous cyclicity (parental animals):

No data availavble

Sperm parameters (parental animals):

No data availavble

Litter observations:

Number and percent of live pups per litter and Mean body weight of live offspring, Proportion of pups born alive and sex of pups born alive were observed.

Postmortem examinations (parental animals):

No data availavble

Postmortem examinations (offspring):

Pattern of testicular descendency in male pups were observed.

Statistics:

Statistical analysis wre performed by using Pairwise comparisons for Fertility of Pairs During Continuous Breedins, Litters per Fertile Pair and Litter Size (Live offsprins) per Fertile Pair by using Chi square Pairwise comparisons .

Reproductive indices:

Fertility, No. Fertile/ No. Cohabited and litters per pair were observed.

Offspring viability indices:

Viability indices were observed.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment related sign of toxicity were observed in treated rats as compared to control.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

Whe treated with 100 and 250 mg/kg/day, 2 male and 2 female were died as compared to control.
Whe treated with 500 mg/kg/day, 4 rats were died as compared to control.
The cause of death varied from case to case but it was neither chemical nor dose related.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No effect was observed body weight of treated rats as compared to control.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

.

Details on results (P0)

No effect on Fertility Index were observed on treated rats as compared to control.
Significant decrase in litters per pair, proportion of pups born alive and sex of pups born alive when treated with 500 mg/kg/day as compared to control

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

reproductive performance

other: No effect observed.

Target system / organ toxicity (P0)

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Details on results (F1)

Mortality:
Significant decrase in number of live pups were observed in 500 mg/kg/day.

Body weight:
Significant decrase in live pup weight and adjusted live pup weight was observed in 500 mg/kg/day treated rats as compared to control.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on survival and body weight were observed.

Target system / organ toxicity (F1)

Critical effects observed:

not specified

Overall reproductive toxicity

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

NOAEL was considered to be 250 mg/kg/dy for F0 and F1 generation when CD-1 albino male and female mice were treated wtih methyl salicylate.

Executive summary:

In a Reproductive toxicity study, CD-1 albino male and female mice were treated with Methyl Salicylate in the concentration of 0, 100, 250 and 500 mg/kg/day by oral gavage. 2 male and 2 female were died in 100 and 250 mg/kg/day dose group and 4 rats were died in 500 mg/kg/day dose group as compared to cont rol.The cause of death varied from case to case but it was neither chemical nor dose related. No treatment related sign of toxicity and change in body weight were observed in treated rats as compared to control. No effect on fertility index were observed but significant decrease in litters per pair, proportion of pups born alive and sex of pups born alive when treated with 500 mg/kg/day as compared to control. In addition, significant decrease in number of live pups, live pup weight and adjusted live pup weight was observed in 500 mg/kg/day treated rats as compared to control. Therefore, NOAEL was considered to be 250 mg/kg/dy for F0 and F1 generation when CD-1 albino male and female mice were treated with methyl salicylate.