Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: via oral route;

NOAEL was in the dose rang of 190-1000 mg/kg bw for test chemical when exposed orally to test animals.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1) which is reported as 0.0063680238mmHg at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 25 micron which is much larger size range compared to the inhalable particulate matter .Thus, exposure to inhalable dust, mist and vapour of the chemical 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
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:
according to
Guideline:
other: as below
Principles of method if other than guideline:
WoE report is based on two repeated dose oral toxicity studies
1. Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical
2. Repeat Oral Dose Toxicity Test was performed for test chemical in rats for 28 by oral gavage to evalute its toxic nature.
GLP compliance:
not specified
Limit test:
no
Species:
other: 1. Rat, 2. mice
Strain:
other: 1. Tif:RAIf, SPF, CD
Sex:
male/female
Details on test animals and environmental conditions:
2. - Source: SPF breeding colony
- Weight at study initiation: Male- 21-30 g and female - 17-25 g
- Fasting period before study: no
- Housing: housed in cages of 15
- Diet (e.g. ad libitum): ground Oxoid pasteurized breeding diet; ad libitum
- Water (e.g. ad libitum): water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21± 1°C
- Humidity (%):50-60%
Route of administration:
other: 1.oral feed 2;Oral gavage
Vehicle:
other: 1. Feed, 2.0.5% sodium carboxymethylcellulose-sodium aqueous solution containing 0.1% Tween 80
Details on oral exposure:
1. PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose level of 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females).

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): Feed
- Concentration in vehicle: 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21,
226, and 2620 mg/kg/day in females)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

2. PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose levels of 0, 100, 200, 400, 800 mg/l (0, 0.2, 0.4, 0.8 or 1.6%)

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): Oxoid pasteurized breeding diet
- Concentration in vehicle: 0, 100, 200, 400, 800 mg/l (0, 0.2, 0.4, 0.8 or 1.6%)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data


2;Details on oral exposure
PREPARATION OF DOSING SOLUTIONS: The 2-Hydroxy-4- (octyloxy) benzophenone was prepared by suspending it in a 0.5% sodium carboxymethylcellulose-sodium aqueous solution containing 0.1% Tween 80 and then storing it in a refrigerator.


VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: 0,20, 140, 1000 mg/kg/day
- Amount of vehicle (if gavage): 10 ml / kg
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
1. Chemical analysis of the feed was done
Duration of treatment / exposure:
1. Chronic
2. sub -acute study
Frequency of treatment:
Daily
Remarks:
1. 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females)
Remarks:
0,20, 140 and 1000 mg / kg bw
No. of animals per sex per dose:
2. Total number of animals- 48
0mg/kg bw:
Male:6 and female:6
20mg/kg bw:
Male:6 and female:6
140mg/kg bw:
Male:6 and female:6
1000mg/kg bw:
Male:6 and female:6
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
1. CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. Mortality, appearance and behavior
DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data
BODY WEIGHT: Yes
- Time schedule for examinations: No data
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: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averag
es from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: No data
OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data
URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data
NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

2. CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Continued surveillance
- Cage side observations checked in table [No.?] were included. Any abnormalities in condition and behav
ior
DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data
BODY WEIGHT: Yes
- Time schedule for examinations: At 4 weeks interval throughout the study
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
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted av
erages 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
OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: wk 13, 26 and 52 and from all surviving mice at wk 80
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10/sex from control group and animals fed 400 and 800 mg/Kg
- Parameters checked in table [No.?] were examined. Haemoglobin concentration and packed cell volume
and counts were made of erythrocytes and total leucocytes. Differential leucocyte counts and reticulocyte
counts were made on the blood from the mice fed on the control diet and from those given diet containing
1.6% Sunset Yellow FCF at wk 26, 52 and 80, and reticulocyte counts were also carried out for these
groups at wk 13.
CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data
URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data
NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data
IMMUNOLOGY: Yes / No / Not specified
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.

2.Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
Time schedule: Once a week
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
General condition, weight and food intake-Once a week
Hematology examination-At the end of planned autopsy
blood biochemical examination- At the end of planned autopsy
Urinalysis- Two days before the dissection at the end of administration

BODY WEIGHT: Yes
- Time schedule for examinations: once a week

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

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

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

OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the time of each planned autopsy
- Anaesthetic used for blood collection: Yes (sodium thiopental, i.p.)
- Animals fasted: No
- How many animals:
0 mg/kg bw: 6 male and 6 female
20 mg/kg bw: 6 male and 6 female
140 mg/kg bw: 6 male and 6 female
1000 mg/kg bw: 6 male and 6 female
Recovery group: 6 male and 6 female

- Parameters checked in table [No.1] were examined.
Following parameter were examined
number of red blood cells (sheath flow DC impedance detection method), white blood cell count (RF / DC impedance detection method), platelet count (Sheep flow DC impedance detection method), hemoglobin concentration (SLS hemoglobin method) and hematocrit value (red blood cell pulse wave height detection method) were analyzed using a multi-item automatic blood cell analyzer (NE-4500: Toa Medical Electronics Co., Wright stained smears) were analyzed using an automated reticulocyte analyzer (R-2000: Toa) using an automatic blood cell analyzer (MICROX HEG-70A: Tateishi Denki Co., Ltd.) and reticulocyte count (argon laser using flow cytometry method) (KC 10 A: Amelung), the prothrombin time (PT: Quick one-step method), the activated partial thromboplastin time (APTT: activated cephaloplastin method) From the results of the examination, mean red blood cell volume (MCV), mean red blood cell hemoglobin amount (MCH) and mean red blood cell hemoglobin concentration (MCHC) were calculated. As a coagulation inhibitor, 3.13% sodium citrate aqueous solution was used for prothrombin time and activated partial thromboplastin time measurement, and EDTA - 2K was used for the other items.



CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the time of necropsy , blood was collected from the posterior vena cava under anesthesia by intraperitoneal administration of sodium thiopental,
- Parameters checked in table [No.?] were examined.
Following parameter were examined
total serum protein, albumin (BCG method), A / G ratio (total protein and Total cholesterol (CES-CO-POD method), urea nitrogen (Urease-GLDH method), creatinine (Jaff method) , glucose (GK-G 6 PDH method), triglyceride (LPL-GK-G 3 PO-POD method) , GTP (Improved SSCC method), GPT (Improve SSCC method), γ-GTP (Improve SSCC method), ALP (Improved method of GSCC), Sodium, Potassium, Crawl (ion selective electrode method) was measured with an automatic analyzer (Model Hitachi 736-10: Hitachi, Ltd.).


URINALYSIS: Yes
- Time schedule for collection of urine: Two days before the dissection at the end of administration
- Parameters checked in table [No.3] were examined.
pH, occult blood, protein, sugar, ketone bodies, bilirubin, urobilinogen (test paper method, Martistics: Miles · Sankyo Co., Ltd.) It was inspected with a urine analyzer (Clinitec 100: Miles · Sankyo Co., Ltd.). As a result, since changes were observed in females at 1000 mg / kg group, accumulated urine was collected for only 21 hours in female, urine volume was measured with a measuring cylinder, specific gravity (refraction method) was measured using a urine density meter (Yuricon-S: (Coulometric titration method) with a full automatic flame photometer (FLAME - 30C / AD - 3: Nippon Bunko Medical Co., Ltd.) with sodium and potassium (flame photometric method) (Model 925: Corning Medical Co., Ltd.).



Sacrifice and pathology:
1.GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

2. GROSS PATHOLOGY: Yes
Necropsy was performed for each animal . Animals abdominal aorta was excised .The weights of the brain, liver, kidney, adrenal gland, thymus, spleen, testis and ovary were measured. In addition to these organs like pituitary, eyeball (including accessory glands), lung, stomach, thyroid (including parathyroid gland), heart, bladder, bone marrow (femur) were collected, .It was fixed in acid buffered formalin solution (eyeball and Harder's gland Davidson solution) and stored.

HISTOPATHOLOGY: Yes ,
Hematoxylin / eosin stained slides were prepared for the heart, liver, spleen, kidney, and adrenal glands of male and female in dose group of 1000 mg / kg/day .In addition, one male in the 20 mg / kg group and two male in the 140 mg / kg group were observed for histopathology. The testes, lung and thymus of one male in the 1000 mg / kg group were examined.
Statistics:
-For the weighing data -Bartlett method
-If variance is uniform, one-way ANOVA followed by comparative test of mean values by Dunnett method or Scheff method
-If variance is not uniform, Kruskal-Wallis test was carried out followed by Dunnett type or Scheff type
-For urinalysis, Armitage's χ ^ 2 test was used.
Clinical signs:
no effects observed
Description (incidence and severity):
1. The test substance did not affect appearance and behavior and was similar in all groups of test.
2.No significant clinical sign were observed at the dose level of 0,20, 140 and 1000 mg / kg bw in treated group compare to control.
Mortality:
no mortality observed
Description (incidence):
1. Mortality was unaffected by the test chemical
2. No mortality were observed at the dose level of 0,20, 140 and 1000 mg / kg bw in treated group compare to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1. 10% decrease in body weight were observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/ day dose group in females.
2. No change in body weight were observed at the dose level of 0,20, 140 and 1000 mg / kg bw in treated group compare to control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
1. Increased food consumption was observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
1.Water consumption showed a dose-related increase in the two highest dose groups (190 and 2300 mg/ Kg/day and 226 and 2620 mg/Kg/day)
Haematological findings:
no effects observed
Description (incidence and severity):
1. Hematology did not show treatment-related effects.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
1. Clinical blood chemistry parameters did not show treatment-related effects.
2;No significant clinical chemistry were observed at the dose level of 0,20, 140 and 1000 mg / kg bw in treated group compare to control.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
1. An increase in urine output was observed in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day)
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
1. In the high dose group, significantly increased organ-to-body weight ratios for liver (p<0.01) were seen in males (2300 mg/Kg/day), and in males and females for kidney (p<0.05) (2300 mg/Kg/day for males and 2620 mg/Kg/day for females). The test substance did not adversely affect other parameters.
2. No significant differences between the organ weights or relative organ weights of the test groups and the corresponding controls.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
1. Macroscopic examinations at necropsy revealed an increased incidence of pancreateic nodules and masses in the 2300 mg/kg/day males and 2620 mg/Kg/day females.
2. No change due to administration of the test substance was observed. Mild bleaching of the kidney, cysts of the kidneys, enlargement of the adrenal glands, miniaturization of the testes, hemorrhage plaques of the lungs, bleeding of the thymus were observed as an incidental change.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
1. Histopathology revealed statistically significant test article-related neoplastic effects to the pancreas of high dose males and females. Nodular hyperplasia of the exocrine pancreas was observed in 51 of 78 (p<0.001) high dose (2300 mg/Kg/day) males versus 6 of 78 control group males, and in 10 of 79 (p<0 .05) high dose (2620 mg/Kg/day) females versus 1 of 78 control group females. Other non-neoplastic lesions seen in the dosed animals were not related to treatment with FWA-5.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
1. Exocrine pancreas adenoma, a benign tumor, was observed in males of the 5,000 and 50,000 ppm dose groups at an incidence of 2/79 and 18/78 (p<0.05), respectively, compared with 0/78 in control. Pancreatic carcinoma, a malignant tumor, was also observed in 2/78 high-dose males and although not statistically significantly increased, the rarity of this tumor and the treatment-related finding of adenomas in this group suggest the carcinomas could be related to the treatment. In females, adenomas in exocrinepancreas occurred only in the high dose (2620 mg/Kg/day) group (2/79) and were within the historical control range; carcinomas were not observed in any of the females.
Other effects:
not specified
Dose descriptor:
NOAEL
Remarks:
1
Effect level:
190 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
haematology
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Remarks on result:
other: No effect observed
Dose descriptor:
NOAEL
Remarks:
1
Effect level:
226 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
haematology
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Remarks on result:
other: No effect observed
Dose descriptor:
NOAEL
Effect level:
1 000 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect were observed at this dose.
Remarks on result:
other: No toxic effect were 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
Conclusions:
NOAEL was in the rang of 190-1000 mg/kg bw for test chemical when exposed orally to test animals.
Executive summary:

The data available for the test chemical was reviewed to determine the toxic nature of 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1)repeated exposure by oral route. The study is as mentioned below:

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using male and female Tif:RAIf, SPF strain rats. The test chemical was mixed with feed at dose levels of 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females). During the chronic study period, the test animals were observed for mortality, clinical signs, changes in body weight, food and water consumption, urinanalysis, hematology and clinical chemistry parameters.The test substance did not affect appearance and behavior and was similar in all groups of test. Mortality was unaffected by the test chemical. 10% decrease in body weight were observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females. Increased food consumption was observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females. Water consumption showed a dose-related increase in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day) and was associated with corresponding urine output. Hematology and chemistry parameters did not show treatment-related effects. An increase in urine output was observed in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day). In the high dose group, significantly increased organ-to-body weight ratios for liver (p<0.01) were seen in males (2300 mg/Kg/day), and in males and females for kidney (p<0.05) (2300 mg/Kg/day for males and 2620 mg/Kg/day for females). The test substance did not adversely affect other parameters. Macroscopic examinations at necropsy revealed an increased incidence of pancreateic nodules and masses in the 2300 mg/kg/day males and 2620 mg/Kg/day females. Histopathology revealed statistically significant test article-related neoplastic effects to the pancreas of high dose males and females. Nodular hyperplasia of the exocrine pancreas was observed in 51 of 78 (p<0.001) high dose (2300 mg/Kg/day) males versus 6 of 78 control group males, and in 10 of 79 (p<0.05) high dose (2620 mg/Kg/day) females versus 1 of 78 control group females. Other non-neoplastic lesions seen in the dosed animals were not related to treatment with FWA-5. Exocrine pancreas adenoma, a benign tumor, was observed in males of the 5,000 and 50,000 ppm dose groups at an incidence of 2/79 and 18/78 (p<0.05), respectively, compared with 0/78 in control. Pancreatic carcinoma, a malignant tumor, was also observed in 2/78 high-dose males and although not statistically significantly increased, the rarity of this tumor and the treatment-related finding of adenomas in this group suggest the carcinomas could be related to the treatment. In females, adenomas in exocrine pancreas occurred only in the high dose (2620 mg/Kg/day) group (2/79) and were within the historical control range; carcinomas were not observed in any of the females. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 190 mg/kg/day for males and 226 mg/kg/day for females when they were exposed to the test chemical during the chronic exposure period.

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using male and femaleCrj:CD (SD) strain rats. The test chemical was administrated by oral gavage at dose levels of0,20, 140 and 1000 mg / kg bw. During the subacute study period, the test animals were observed for mortality, clinical signs, changes in body weight, food, urinanalysis, hematology and clinical chemistry parameters, gross pathology and histopathology. The test substance did not affect appearance and behavior and was similar in all groups of test. Mortality was unaffected by the test chemical. No significant effect were observed on the body weight, food, urinanalysis, hematology and clinical chemistry parameters, gross pathology and histopathology at all dose levelof 0,20, 140 and 1000 mg / kg bw in treated group compare to control. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/kg/day for males and females when they were exposed to the test chemical during the 28 days exposure period by oral gavage.

 

Based on the data available from the test chemical 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1) does not exhibit repeated dose oral toxicity in the range of 190-1000 mg/kg bw. Hence the test chemical is not likely to classify as a repeated dose oral toxicity as per the criteria mentioned in CLP regulation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
WoE prepared from two well qualified publication.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity: via oral route;

The data available for the test chemical was reviewed to determine the toxic nature of 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1)repeated exposure by oral route. The study is as mentioned below:

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using male and female Tif:RAIf, SPF strain rats. The test chemical was mixed with feed at dose levels of 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females). During the chronic study period, the test animals were observed for mortality, clinical signs, changes in body weight, food and water consumption, urinanalysis, hematology and clinical chemistry parameters.The test substance did not affect appearance and behavior and was similar in all groups of test. Mortality was unaffected by the test chemical. 10% decrease in body weight were observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females. Increased food consumption was observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females. Water consumption showed a dose-related increase in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day) and was associated with corresponding urine output. Hematology and chemistry parameters did not show treatment-related effects. An increase in urine output was observed in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day). In the high dose group, significantly increased organ-to-body weight ratios for liver (p<0.01) were seen in males (2300 mg/Kg/day), and in males and females for kidney (p<0.05) (2300 mg/Kg/day for males and 2620 mg/Kg/day for females). The test substance did not adversely affect other parameters. Macroscopic examinations at necropsy revealed an increased incidence of pancreateic nodules and masses in the 2300 mg/kg/day males and 2620 mg/Kg/day females. Histopathology revealed statistically significant test article-related neoplastic effects to the pancreas of high dose males and females. Nodular hyperplasia of the exocrine pancreas was observed in 51 of 78 (p<0.001) high dose (2300 mg/Kg/day) males versus 6 of 78 control group males, and in 10 of 79 (p<0.05) high dose (2620 mg/Kg/day) females versus 1 of 78 control group females. Other non-neoplastic lesions seen in the dosed animals were not related to treatment with FWA-5. Exocrine pancreas adenoma, a benign tumor, was observed in males of the 5,000 and 50,000 ppm dose groups at an incidence of 2/79 and 18/78 (p<0.05), respectively, compared with 0/78 in control. Pancreatic carcinoma, a malignant tumor, was also observed in 2/78 high-dose males and although not statistically significantly increased, the rarity of this tumor and the treatment-related finding of adenomas in this group suggest the carcinomas could be related to the treatment. In females, adenomas in exocrine pancreas occurred only in the high dose (2620 mg/Kg/day) group (2/79) and were within the historical control range; carcinomas were not observed in any of the females. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 190 mg/kg/day for males and 226 mg/kg/day for females when they were exposed to the test chemical during the chronic exposure period.

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using male and femaleCrj:CD (SD) strain rats. The test chemical was administrated by oral gavage at dose levels of0,20, 140 and 1000 mg / kg bw. During the subacute study period, the test animals were observed for mortality, clinical signs, changes in body weight, food, urinanalysis, hematology and clinical chemistry parameters, gross pathology and histopathology. The test substance did not affect appearance and behavior and was similar in all groups of test. Mortality was unaffected by the test chemical. No significant effect were observed on the body weight, food, urinanalysis, hematology and clinical chemistry parameters, gross pathology and histopathology at all dose levelof 0,20, 140 and 1000 mg / kg bw in treated group compare to control. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/kg/day for males and females when they were exposed to the test chemical during the 28 days exposure period by oral gavage.

 

Based on the data available from the test chemical 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1) does not exhibit repeated dose oral toxicity in the range of 190-1000 mg/kg bw. Hence the test chemical is not likely to classify as a repeated dose oral toxicity as per the criteria mentioned in CLP regulation.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1) which is reported as 0.0063680238mmHg at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 25 micron which is much larger size range compared to the inhalable particulate matter .Thus, exposure to inhalable dust, mist and vapour of the chemical 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Based on the data available for the target chemical 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1)does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical 1,4-phenylene bis[(4-phenoxyphenyl)-methanone]; [4-(4-phenoxybenzoyl)phenyl](4-phenoxyphenyl)methanone (54299-17-1)does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.