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Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for 1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1) was considered to be in range of 500-1000mg/kg bw/day .When male and female rats were treated with 1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1)orally. Thus, comparing this value with the criteria ofCLP regulation 1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1)isnot likely to classify as reproductive toxicant.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data of read across substances
Justification for type of information:
Weight of evidence approach based on structurally similar chemicals
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats.
Reproductive and developmental toxicity study of test material was performed on rats.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Species:
rat
Strain:
other: 1.Tif:RAI f (SPF) hybrid 2.Sprague-Dawley
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:9 weeks
- Weight at study initiation:
- Fasting period before study: Females were caged individually in Macrolon cages containing standardized soft wood bedding material.
- Housing:
- Diet (e.g. ad libitum): standard pelleted rat food (Nafag No. 890; Gossau, Switzerland) ad libitum
- Water (e.g. ad libitum):water ad libitum
- Acclimation period:7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3 °C
- Humidity (%):30-70%,
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): daily cycle of 12 hours light

Route of administration:
oral: gavage
Vehicle:
other: 1. aqueous solution of carboxymethylcellulose (0.5% w/w).2.corn oil
Details on exposure:
1.Details on exposure
Test material dissolved in aqueous solution of carboxymethylcellulose (0.5% w/w).
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test material dissolved in aqueous solution of carboxymethylcellulose (0.5% w/w).

- Concentration in vehicle:0,1000mg/kg bw/day
- Amount of vehicle (if gavage): 20ml/kg
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
1.- M/F ratio per cage:one male rat was housed with 3 females
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:vaginal lavage showed spermatozoa or a vaginal plug was observed; this was designated as gestation day zero
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available
- After successful mating each pregnant female was caged (how): an individual
- Any other deviations from standard protocol:No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Study 1&2
10 days (6 through day 15 of gestation)
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
Study 1
0, 1000mg/kg bw/day
Study 2.
0,50, 200, 500 mg/kg/day
No. of animals per sex per dose:
Study 1.
Total :48
0 mg/kg :24 female
1000mg/kg:24 female
Study 2.
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
Parental animals: Observations and examinations:
1&2 CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- 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 / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

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):
Study 1& 2
SACRIFICE
All animals survived to necropsy on gestation day 21
GROSS NECROPSY
- 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):
Study 1& 2
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

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

HISTOPATHOLOGY / ORGAN WEIGTHS
About one-half of each litter was taken for visceral evaluation by the Wilson slicing technique after fixation. The remaining fetuses from each litter were fixed, cleared with KOH solution and then treated with alizarin red S for examination of skeletal features.
Statistics:
Study 2.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
Clinical signs:
no effects observed
Description (incidence and severity):
Study 1.There were no remarkable cage-side observations during the study.
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:
no mortality observed
Description (incidence):
Study 1.No effect on survival of treated rats were observed as compared to control.
2 deaths occurred at 500 mg/kg
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Study 1.No effect on body weight of treated rats was observed as compared to control.
Statistically reduced maternal weight gain were observed at 200 and 500 mg/kg/d.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Study 1.No effect on food consumption of treated rats was observed as compared to control.
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:
no effects observed
Description (incidence and severity):
Study 1.All animals survived to necropsy on gestation day 21, except for one dam from the treated group, found dead on gestation day 15. Necropsy revealed no pathological findings. Necropsy of all other animals did not reveal adverse effects or abnormal findings
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Study 1.The number of implantation sites and preimplantation losses were comparable in the two groups. Early resorption rate was not affected by treatment, and there were no late resorptions, abortions or dead fetuses. Thus, the number of viable fetuses was comparable in the two groups. Statistical analysis of these endpoints did not show significant differences from the control group.
There was no evidence for an impairment of reproductive functions in animals
2.No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations
Dose descriptor:
NOAEL
Effect level:
> 500 - <= 1 000 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
histopathology: non-neoplastic
reproductive performance
Remarks on result:
other: No effects on reproductive performance
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
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):
1.body weights were not affected by treatment.
2.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):
1.The findings observed during fetal examinations were of equal frequency in the control and treated groups; thus, treatment-related effects on fetal external, visceral, or skeletal development did not occur in this study.
2.No significant increases were observed in incidence of malformations or variations at any treatment level.
Histopathological findings:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Fetal sex ratios were not affected by treatment.
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 500 - <= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality
body weight and weight gain
gross pathology
Remarks on result:
other: No developmental toxic effects observed
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
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
Conclusions:
In reproductive and developmental toxicity study , NOAEL was considered to be in range of 500-1000mg/kg bw/day as no effects on reproductive and developmental parameters were observed . When female rats were treated wtih 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1) orally.
Executive summary:

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1).The studies are as mentioned below:

Study 1.

In reproductive and developmental toxicity study , femaleTif:RAI f (SPF) hybrid ratsrats were treated wtih test material in dose concentration 0,1000mg/kg orallyfrom day 6 through day 15 of gestation, inclusive.Test materialwas administered by gavage in an aqueous solution of carboxymethylcellulose (0.5% w/w). The control group received the vehicle solution. The dose volume in both groups was 20 ml/kg body weight, based on the daily body weight.24 females in each group, a proven fertile male rat of the same strain was placed in a mating cage with 3 females each. The female was removed and indicated as pregnant if vaginal lavage showed spermatozoa or a vaginal plug was observed; this was designated as gestation day zero.All the animals observed for body weight ,food consumption and mortality. There were no remarkable cage-side observations during the study. Maternal body weights and food consumption were not affected by treatment. All animals survived to necropsy on gestation day 21, except for one dam from the treated group, found dead on gestation day 15. Necropsy revealed no pathological findings. Necropsy of all other animals did not reveal adverse effects or abnormal findings.Three animals in the control group were not pregnant, and one in the treated group died on gestation day15. Thus, the number of pregnant animals with viable fetuses at necropsy was 21 and 23 for the control and treated group, respectively.

The number of implantation sites and preimplantation losses were comparable with the control groups. Early resorption rate was not affected by treatment, and there were no late resorptions, abortions or dead fetuses. Thus, the number of viable fetuses was comparable with control groups. Statistical analysis of these endpoints did not show significant differences from the control group.Fetal sex ratios and body weights were not affected by treatment. The findings observed during fetal examinations were of equal frequency in the control and treated groups; thus, treatment-related effects on fetal external, visceral, or skeletal development did not occur in this study.Hence,NOAEL was considered to be 1000mg/kg bw/day as no effects on reproductive and developmental parameters were observed. When female rats were treated wtih test material orally.

Study 2.

Reproductive and development toxicity study of  Diphenyl ether(101-84-8) was performed on mated female Sprague Dawley rats according toOECD Test Guideline 414.The test materialmixed 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, and No 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 female Sprague Dawley rats were treated with test material orally.

Based on the data available from different studies,1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1))did not showedreproductive toxicityat dose concentration 500mg/kg bw/day by oral route.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1).The studies are as mentioned below:

Study 1.

In reproductive and developmental toxicity study , femaleTif:RAI f (SPF) hybrid rats were treated wtihtest material in dose concentration 0,1000mg/kg orallyfrom day 6 through day 15 of gestation, inclusive.Test materialwas administered by gavage in an aqueous solution of carboxymethylcellulose (0.5% w/w). The control group received the vehicle solution. The dose volume in both groups was 20 ml/kg body weight, based on the daily body weight.24 females in each group, a proven fertile male rat of the same strain was placed in a mating cage with 3 females each. The female was removed and indicated as pregnant if vaginal lavage showed spermatozoa or a vaginal plug was observed; this was designated as gestation day zero.All the animals observed for body weight ,food consumption and mortality. There were no remarkable cage-side observations during the study. Maternal body weights and food consumption were not affected by treatment. All animals survived to necropsy on gestation day 21, except for one dam from the treated group, found dead on gestation day 15. Necropsy revealed no pathological findings. Necropsy of all other animals did not reveal adverse effects or abnormal findings.Three animals in the control group were not pregnant, and one in the treated group died on gestation day15. Thus, the number of pregnant animals with viable fetuses at necropsy was 21 and 23 for the control and treated group, respectively.

The number of implantation sites and preimplantation losses were comparable with the control groups. Early resorption rate was not affected by treatment, and there were no late resorptions, abortions or dead fetuses. Thus, the number of viable fetuses was comparable with control groups. Statistical analysis of these endpoints did not show significant differences from the control group.Fetal sex ratios and body weights were not affected by treatment. The findings observed during fetal examinations were of equal frequency in the control and treated groups; thus, treatment-related effects on fetal external, visceral, or skeletal development did not occur in this study.Hence,NOAEL was considered to be 1000mg/kg bw/day as no effects on reproductive and developmental parameters were observed. When female rats were treated wtihtest material orally.

Study 2.

Reproductive and development toxicity study of  Diphenyl ether(101-84-8) was performed on mated female Sprague Dawley rats according toOECD Test Guideline 414.The test materialmixed 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, and No 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 female Sprague Dawley rats were treated with test material orally.

Based on the data available from different studies,1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1))did not showedreproductive toxicityat dose concentration 500mg/kg bw/day by oral route.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

 

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation 1,4-phenylene bis[(4-phenoxyphenyl)-methan one] (CAS no. 54299 -17 -1)isnot likely to classify as reproductive toxicant.