4-methoxy-N-phenyl-o-toluidine

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

Prenatal development toxicity study

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data from secondary source

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Reproductive and developmental toxicity study of Diphenyl ether

Author:

HPVIS

Year:

2017

Bibliographic source:

HPVIS,2017

Reference 2

Reference Type:

other: Authoritative database

Title:

Reproductive and developmental toxicity study of Diphenyl ether

Author:

GESTIS

Year:

2017

Bibliographic source:

IFA, Institute for Occupational Safety and Health of the German Social Accident Insurance

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Reproductive and developmental toxicity study of Diphenyl ether was performed on Sprague Dawley rats.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Test material

Test material information

Constituent 1

Reference substance name:

1,1'-Oxybis-benzene

Cas Number:

101-84-8

Molecular formula:

C12H10O

IUPAC Name:

1,1'-Oxybis-benzene

Details on test material:

- Name of test material (IUPAC name): 1,1'-Oxybis-benzene
- Common name: Diphenyl ether
- Molecular formula: C12H10O
- Molecular weight: 170.21 g/mol
- Smiles notation: c1(Oc2ccccc2)ccccc1
- InChl: 1S/C12H10O/c1-3-7-11(8-4-1)13-12-9-5-2-6-10-12/h1-10H
- Substance type: Organic

Specific details on test material used for the study:

- Name of test material: Diphenyl oxide
- IUPAC name: 1,1'-Oxybis-benzene
- Molecular formula: C12H10O
- Molecular weight: 170.21 g/mol
- Substance type: Organic
- Physical state: No data
- Purity: No data
- Impurities (identity and concentrations): No data

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

female

Details on test animals or test system and environmental conditions:

No data available

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material 73.5% Diphenyl ether & 26.5% biphenyl mixed in corn oil.
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 50, 200, 500 mg/kg/day - Amount of vehicle (if gavage): 5ml/kg

- Lot/batch no. (if required): No data available
- Purity: No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

10 days ( on gestation days 6-15)

Frequency of treatment:

daily

Details on study schedule:

No data available

Doses / concentrations

Remarks:

0,50, 200, 500 mg/kg/day

No. of animals per sex per dose:

Total:96
0 mg/kg bw/day:24
50mg/kg bw/day:24
200mg/kg bw/day:24
500mg/kg bw/day:24

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Examinations

Parental animals: Observations and examinations:

Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule:


BODY WEIGHT: Yes
Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


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

OTHER:

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

SACRIFICE
- Maternal animals: yes
GROSS NECROPSY: yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

GROSS NECROPSY: yes
- Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations

Statistics:

Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01.

Reproductive indices:

No data available

Offspring viability indices:

No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

2 deaths occurred at 500 mg/kg

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Statistically reduced maternal weight gain were observed at 200 and 500 mg/kg/d.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Statistically reduced food consumption were observed at 200 and 500 mg/kg/d.

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:

no effects observed

Description (incidence and severity):

No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

Remarks on result:

other: No toxic effects observed

2

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effects on reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

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:

no effects observed

Description (incidence and severity):

Mean litter weights in treated and control groups were similar

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:

no effects observed

Description (incidence and severity):

increases were observed in incidence of malformations or variations at any treatment level.

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)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

gross pathology

Remarks on result:

other: No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw.

Target system / organ toxicity (F1)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 50 mg/kg/day, and No indications of any influence on reproductive parameters or damage to reproductive organs were found and No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw. Hence the dose-level of 500 mg/kg/day was considered to be the NOAEL for embryo-foetal toxicity and reproductive toxicity .When female Sprague Dawley rats were treated with Diphenyl ether (101-84-8) orally.

Executive summary:

Reproductive and development toxicity study of  Diphenyl ether(101-84-8) was performed on mated female SpragueDawley rats according toOECD Test Guideline 414. The test material73.5%Diphenyl ether  & 26.5% biphenyl mixed in corn oil at volume of 5 ml/kg wereadministered in dose concentration 0,50, 200, 500 mg/kg/day on gestation days 6-15by oral gavage route. .96 rats were divided as 24 rats /dose group

.Animals was checked daily for clinical signs. Food consumption and body weight were recorded; the dams were sacrificed and subjected to a macroscopic examination. Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations. Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01. Two deaths occurred at 500 mg/kg. Statistically reduced maternal weight gain and food consumption were observed at 200 and 500 mg/kg/d. Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined. No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations. Mean litter weights in treated and control groups were similar. No significant increases were observed in incidence of malformations or variations at any treatment level. Therefore No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 50 mg/kg/day, andNo indications of any influence on reproductive parameters or damage to reproductive organs were foundand No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw. Hencethe dose-level of 500 mg/kg/day was considered to be the NOAEL for embryo-foetal toxicity and reproductive toxicity .When femaleSprague Dawley rats were treated withDiphenyl ether(101-84-8)orally.