p-toluic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are two effects being displayed in this study. Firstly the reproductive performance/implantation in females with treatment related adverse effects at 300 mg/kg bw and above. The other effect is in the male sex organs at 1000 mg/kg bw. However the NOAEL 100 mg/kg bw is based on the effects seen in females.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: Until copulation confirmed
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males: 14 days before mating until sacrifice (pre-mating and mating periods; 32 days total)
Females: 14 days before mating until the third day after delivery (pre-mating, mating and gestation periods)
Male: 43 days; Female: 40-53 days

Frequency of treatment:

Daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

13

Control animals:

yes, concurrent vehicle

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In female animals, reduced body weight gain during late pregnancy and lactation periods was found in the groups treated with 300 mg/kg bw/day dose and higher.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

. Fertility index at 1000 mg/kg bw/day was sifnificantly decreased. The implantation index and the number of pups born were significantly reduced in the groups treated with 300 mg/kg bw/day and higher. The reduction in the number of live pups in the 1000 mg/kg bw/day group was observed on postnatal days (PNDs) 0 and 4.

Male animals were sacrificed and necropsied on Day 43, and the testis, epididymis, ventral prostate and seminal vesicle were collected. Testis and epididymis were weighed. All females delivered were sacrificed and necropsied on PND 4, and the ovary, uterus and vagina were collected.
No abnormalities were observed in delivery and lactation conditions, and the treatment also did not change a gestation length and the indices of birth rate, live birth rate and viability on PND 4. In addition, it did not affect indices of development and growth of the offspring, such as sex ratio and body weight on PND 0, 4, and body morphology.

Key result

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

other: Implantation index.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

reproductive performance

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (actual dose received)

System:

female reproductive system

Organ:

uterus

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Histopathological findings: neoplastic:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day

Treatment related:

yes

Relation to other toxic effects:

reproductive effects in the absence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

not specified

With regard to reproductive toxicity, a decrease in the implantation index and the number of pups was noted in the groups treated with 300 mg/kg bw/day dose and higher. In male animals, histopathological examination found no abnormalities in the testis. However, a significant increase in the number of cauda epididymal lumen with decreased number of spermatozoa and slightly increased cell debris was observed in the epididymis of the 1000 mg/kg bw/day group.

Conclusions:

There are two effects being displayed in this study. Firstly the reproductive performance/implantation in females with treatment related adverse effects at 300 mg/kg bw and above. The other effect is in the male sex organs at 1000 mg/kg bw. However the NOAEL 100 mg/kg bw is based on the effects seen in females.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Klimisch 1

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Quality of whole database:

Klimisch 1

Justification for classification or non-classification

There are two effects being displayed in this study. Firstly the reproductive performance/implantation in females with treatment related adverse effects at 300 mg/kg bw and above. The other effect is in the male sex organs at 1000 mg/kg bw. However the NOAEL 100 mg/kg bw is based on the effects seen in females.

On this basis no classification will be effected.