4-methoxyphenylacetic acid

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

Carcinogenic effect

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Study report from National Cancer Institute

Data source

Reference

Reference Type:

secondary source

Title:

Evaluation of Carcinogenicity, Teratogenecity &Mutagenic Activities of Selected Pesticides and Industrial Chemicals.

Author:

NTRL report

Year:

1968

Bibliographic source:

NTRL report, PB223159,1968

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Long term toxicity and carcinogenicity study of 4-methoxyphenylacetic acid in mice.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-methoxyphenylacetic acid

EC Number:

203-166-4

EC Name:

4-methoxyphenylacetic acid

Cas Number:

104-01-8

Molecular formula:

C9H10O3

IUPAC Name:

2-(4-methoxyphenyl)acetic acid

Test material form:

solid: crystalline

Details on test material:

- Name of test material (as cited in study report): P-methoxy phenyl acetic acid
- Molecular formula (if other than submission substance): C9H10O3
- Molecular weight (if other than submission substance): 166.175 g/mole
- Smiles notation (if other than submission substance): c1(ccc(OC)cc1)CC(O)=O
- InChl (if other than submission substance): 1S/C9H10O3/c1-12-8-4-2-7(3-5-8)6-9(10)11/h2-5H, 6H2, 1H3, (H,10,11)
- Substance type: Organic
- Physical state: Solid

Specific details on test material used for the study:

- Name of test material (as cited in study report): (4-methoxyphenyl)acetic acid
- Molecular formula: C9H10O3
- Molecular weight: 166.175 g/mole
- Substance type: Organic

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

female

Details on test animals or test system and environmental conditions:

- Source:Cumberland View Farms
- Age at study initiation: 7 dyas
- Weight at study initiation: 10-19 gms
Fasting period before study:
- Housing: Animals were 6 mice to a cage. 2160 mice couli be housed in each room.
- Diet (e.g. ad libitum): food , ad libitum
- Water (e.g. ad libitum): water, ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr): A dual duct high velocity sy~tem was used for heating, ventilation and air conditioning.Unidirectional air-flow minimized room to room contamination with absolute filtration of all incoming air to remove particulate matter of 0.3 micron diameter or greater.
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: 1966 To:1968

Administration / exposure

Route of administration:

other: oral administration by stomach tube and after dose is administer through diet.

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: Diet(ground feed) and 0.5% gelatin

Details on exposure:

oral administration by stomach tube from day 7 to 28 and after dose is administer through diet for 18 months

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

18 months

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

0 and 215 mg/kg bw/day

No. of animals per sex per dose:

Total: 150
0 mg/kg bw 18 Females
0 mg/kg bw 18 Females
215 mg/kg bw 18 Females

Positive control
Ethyl carbamate: 24 Females
Amitrol: 18 Females
E:thylene imine: 18 Females
Aramite: 18 Females
Dihydrosafrole: 18 Females
Safrole: 18 Females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The basic concept of the dosage choice was the use of a maximum tolerated dose. The calculated dose was not adjusted to the changing body weight during the three weeks of stomach tubing but a single adjustment was made at the time of conversion from stomach tube to mixture in the feed.
- Rationale for animal assignment (if not random): Dosing of individual mice was based on the average weight within a single group and, in the case of repetitive administration, was based on starting weights and not adjusted as the study continued.( An exception to this was the recalculation in the definitive study, at the time of weaning when administration was converted from daily stomach tubing to incorporation in the diet.)

Positive control:

Ethyl carbamate, Amitrol, E:thylene imine, Aramite, Dihydrosafrole and Safrole were used as positive contorl.

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Daily
- Cage side observations checked in table [No.?] were included: Mortality and morbidity were observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: palpated weekly at time of weighing for enlargement of liv,~r and spleen, or any subcutaneous tumor.

BODY WEIGHT: Yes
- Time schedule for examinations: six animals in each cage were weighed once a week.

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

Gross pathology and histopathology were examined.

Postmortem examinations (offspring):

No data available

Statistics:

Chi square test &Yates Correction were used

Reproductive indices:

No data available

Offspring viability indices:

No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, non-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

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Details on results (P0)

MORTALITY (PARENTAL ANIMALS): No effect on survival of treated female mice were observed as compared to control.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Body weight gain was observed with the increase in duration of treatment.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS):No data available

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS):No data available

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS):No data available

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):Disrupted sexual function

ORGAN WEIGHTS (PARENTAL ANIMALS):No data available

GROSS PATHOLOGY (PARENTAL ANIMALS): No gross pathological changes were observed in treated female mice.

HISTOPATHOLOGY (PARENTAL ANIMALS): No fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control.

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

> 215 other: mg/kg

Based on:

test mat.

Sex:

female

Basis for effect level:

mortality

gross pathology

histopathology: non-neoplastic

Target system / organ toxicity (P0)

Critical effects observed:

not specified

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

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

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Effect levels (P1)

Remarks on result:

not measured/tested

Target system / organ toxicity (P1)

Critical effects observed:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

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

Effect levels (F1)

Remarks on result:

not measured/tested

Target system / organ toxicity (F1)

Critical effects observed:

not specified

Results: F2 generation

General toxicity (F2)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

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 (F2)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:

not specified

Effect levels (F2)

Remarks on result:

not measured/tested

Target system / organ toxicity (F2)

Critical effects observed:

not specified

Overall reproductive toxicity

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

NOAEL was considered to be > 215 mg/kg bw when B6C3F1 female mice by using (4-methoxyphenyl)acetic acid for 18 months.

Executive summary:

In a reproductive toxicity study, B6C3F1 female mice were treated with (4-methoxyphenyl)acetic acid in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administer through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, no fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6C3F1 female mice by using (4-methoxyphenyl)acetic acid for 18 months.