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Description of key information

Repeated Dose toxicity: Oral route
LOAEL was considered to be 3000 ppm (150 mg/kg/day) and NOAEL was 1000 ppm (50 mg/kg/day) when F344/ N male and female rat treated with 2-Biphenylamine.
Repeated Dose toxicity: Inhalation route
The chemical biphenyl-2-ylamine has low vapour pressure of 0.000117 mm Hg at 25 deg C as well as particle size that are larger than the inhalable particulates. In addiiton, the use fo the chemical does not indicate the likelyihood of epeated exposure by the inhalation route. Thus, this end point was considered for waiver since the chemical is not expected to exhibit adverse effects by the repeated inhaltion route of exposure.

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:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from NTP Report
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Chronic repeated dose toxicity study of Technical grade 2-Biphenylamine in rat orally.
GLP compliance:
not specified
Limit test:
yes
Species:
rat
Strain:
other: F344 /N
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Frederick Cancer Research
Center (Frederick, MD)
- Age at study initiation: 5 weeks
- Weight at study initiation:No data
- Fasting period before study:No data
- Housing: 5 per cage, Polycarbonate, Lab Products, Inc., Replaced twice per week, Bedded on Aspen Bed®,American Excelsior,Beta Chips® Agway Corp., Changed twice per week, Cage Fillers of Nonwoven polyester filter sheets, Snow Filtration were provided.
- Diet : Wayne Lab Blox® meal, Allied M ills, Inc. (Chicago, IL). ad libitum
- Water : Water Available in water bottles replaced twice per week, ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2°-32.2°C.
- Humidity (%): Humidity uncontrolled.
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): Fluorescent lighting provided 12 hours per day.

IN-LIFE DATES: From: To: No data available
Route of administration:
oral: feed
Vehicle:
other: Wayne Lab Blox® meal
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 2-Biphenylamine mix with Wayne Lab Blox® feed in Patterson-Kelly® Twin Shell Blender.

DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Wayne Lab Blox® feed
- Storage temperature of food: 4°C

VEHICLE
- Justification for use and choice of vehicle (if other than water): Wayne Lab Blox® feed
- Concentration in vehicle: 0, 300, 1,000, 3,000, 10,000 and 30,000 ppm
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by using gas chromatography
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 300, 1,000, 3,000, 10,000 and 30,000 ppm (0,15, 50, 150, 500 and 1500 mg/kg/day)
Basis:
nominal in diet
No. of animals per sex per dose:
Total: 120
0 ppm: 10 male, 10 female
300 ppm: 10 male, 10 female
1000 ppm: 10 male, 10 female
3000 ppm: 10 male, 10 female
10000 ppm: 10 male, 10 female
30000 ppm: 10 male, 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): Animal were assigned to test groups so that average cage weights approximately equal for all animals of same sex and species.
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included. Mortality and morbidity were observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly.

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

FOOD EFFICIENCY: No data available
- 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 data available


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


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


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 1, 4 and 13 weeks
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: All animals were examined.
- Parameters checked in table [No.?] were examined: Red blood cell count and hematocrit and differential leucocyte counts were examined.

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Gross abnormalities were observed.

HISTOPATHOLOGY: Yes
All tissues were fixed for a minimum of 48 hours in 10% neutral buffered formalin, embedded in parablast, sectioned, and stained with hematoxylin and eosin. Selected kidneys were cut in 4 µ sections and stained with Von Kossa, Mallory trichrome, MacManus-PAS, or Prussian blue solutions.

Organ examined:
Skin, mandibular lymph node, mammary gland, salivary gland, thigh muscle, sciatic nerve, sternebrae including marrow, costochondral junction (rib), thymus, larynx, trachea, lungs and bronchi, heart, thyroids, parathyroid, lymph nodes, esophagus, stomach, duodenum, jejunum, ileum, colon, cecum, rectum, mesenteric lymph node, liver, pancreas, spleen, kidneys, adrenal, urinary bladder, seminal vesicles, prostate, testes, ovaries, uterus, brain, pituitary, spinal cord and eyes were observed.
Other examinations:
No data available
Statistics:
For the hematology data, Jonckee.re's test was employed to assess the significance of dose response trend-so When a significant trend was detected, pairwise comparisons between dosed and control animals were made by the Mann-Whitney U-test.
Clinical signs:
no effects observed
Description (incidence and severity):
One male died in 300 ppm and five female died in 30000 ppm dose group. Deaths were not treatment related.
Mortality:
no mortality observed
Description (incidence):
One male died in 300 ppm and five female died in 30000 ppm dose group. Deaths were not treatment related.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When treated with 30000 ppm, dose-related decrease in body weight gain was observed in male and female rats as compared to control.
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:
effects observed, treatment-related
Description (incidence and severity):
When treated with 10000 and 30000 ppm, in male and female rat Significant decrease were observed in hemoglobin and RBC level, Significant decrease in hematocrit level in female as compared to control and Significant increase in leucocyts.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Splenomegaly was observed in male and female rat when treated with 30000 ppm as compared to control.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
Incidence of splenomegaly and lesser depression of weight gain relative to control indicate that Technical grade 2-Biphenylamine was toxic to rats.

Haematology:
Leucocyts level were diminish with time by week 13 may be due to activation of a hemeostatic mechanism in these animals.
When treated with 3000 ppm, in male and female rat Significant decrease were observed in hemoglobin and RBC level as compared to control.

Histopathology:
Erythroid hyperplasia of the bone marrow, included cystic tubular degeneration and papillary necrosis and chronic nephritis, Transitional- cell hyperplasia of the urinary bladder was observed in male and female rat when treated with 30000 ppm as compared to control.
Hemosiderosis, congestion and extramedullary hematopoiesis were observed in spleens of male and female treated with 3000 ppm and in female rat treated with 10000 ppm as compared to control.
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effect on hematology and histopathology
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect on survival, body weight, Haematology, Gross pathology and Histopathology
Critical effects observed:
not specified
Conclusions:
LOAEL was considered to be 3000 ppm (150 mg/kg/day) and NOAEL was 1000 ppm (50 mg/kg/day) when F344/ N male and female rat treated with 2-Biphenylamine.
Executive summary:

In a chronic repeated dose toxicity study, F344/ N male and female rat treated withTechnical grade 2-Biphenylamine in the concentration of 0, 300, 1,000, 3,000, 10,000 and 30,000 ppm orally in diet.

Dose-related decrease in body weight gain was observed in male and female and Significant decrease were observed in hemoglobin and RBC level, Significant decrease in hematocrit level in female were observed when treated with 10,000 and 30,000 ppm. In addition, Splenomegaly, Erythroid hyperplasia of bone marrow, included cystic tubular degeneration and papillary necrosis and chronic nephritis, Transitional- cell hyperplasia of the urinary bladder in male and female and Hemosiderosis, congestion and extramedullary hematopoiesis were observed in spleens of female rat.

Therefore, LOAEL was considered to be 3000 ppm (150 mg/kg/day)and NOAEL was 1000 ppm (50 mg/kg/day)when F344/ N male and female rat were treated with2-Biphenylamine orally in diet for 13 weeks.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is of K2 level obtained from NTP Report

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated Dose toxicity: Oral route

Studies for repeated dose toxicity: oral route from reliable sources having Klimisch rating 2 were reviewed for the target and read across substance

The summary of the results are presented below:

 

Sr. No

End point

Value

Species

Route

Duration

Effects

Remarks

1.     

LOAEL

 

 

 

NOAEL

150 mg/ kg bw/ d

 

 

50 mg/ kg bw/ d

Rat

Oral: feed

13 days

Adverse Effect on body weight and gross pathology

 

No effect on survival, body weight, and gross pathology

Experimental data for target chemical

2.     

LOAEL

 

 

 

NOAEL

150 mg/ kg bw/ d

 

 

50 mg/ kg bw/ d

Rat

Oral: feed

13 weeks

Effect on hematology and histopathology

 

No effect on survival, body weight, Haematology, Gross pathology and Histopathology

Experimental data for target chemical

3.     

 LOAEL

 

600 mg/ kg bw/ d (male)

 

2000 mg/ kg bw/ d (female)

Mouse

Oral: feed

13 days

Effect on body weight and gross pathology

Experimental data for target chemical

4.     

LOAEL

500 mg/ kg bw/ d

 

Mouse

Oral: feed

13 weeks

Effect on hematology and histopathology

 

Experimental data for target chemical

5.     

NOAEL

428 mg/ kg bw/ d (male)

 

143 mg/ kg bw/ d (female)

 

Mouse

Oral: feed

103 weeks

No effect on survival, Clinical signs, Body weight, Food consumption, Gross pathology and histopathology

Experimental data for RA CAS: 2185-92-4

6.     

NOAEL

50 mg/ kg bw/ d (male)

 

150 mg/ kg bw/ d (female)

 

Rat

Oral: feed

103 weeks

No effect on survival, Clinical signs, Body weight, Food consumption and histopathology

Experimental data for RA CAS: 2185-92-4

 

Based on the studies summarized in the above table it can be observed that NOAEL value varies from 50 mg/Kg bw/ d. in rats and mice for target chemical, whereas the lowest effect observed value (LOAEL) value range is 150-2000 mg/kg bw/d. The effects observed on these doses was listed as follows:

 

·        Adverse Effect on body weight and gross pathology

·        Effect on hematology and histopathology

·        No effect on survival, body weight, Haematology, Gross pathology and Histopathology

·        No effect on survival, Clinical signs, Body weight, Food consumption, Gross pathology and histopathology.

 

 

Since no effective dose value (NOAEL) is 50 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 90-41-5 is considered to be not toxic to repeated dose via oral route for the above mentioned dose. The NOAEL values for the similar substance also suggest that there will not be the substance is not likely to be hazardous on repeated administration.

Repeated Dose toxicity: Inhalative route

The chemical biphenyl-2-ylamine has low vapour pressure of 0.000117 mm Hg at 25 deg C as well as particle size that are larger than the inhalable particulates. In addiiton, the use fo the chemical does not indicate the likelyihood of epeated exposure by the inhalation route. Thus, this end point was considered for waiver since the chemical is not expected to exhibit adverse effects by the repeated inhaltion route of exposure.

Repeated Dose toxicity: Dermal route

The chemical 2-Biphenylamine finds use in manufacture of fine chemicals and formulation of preparations. Thus, the repeated exposure by the dermal route is unlikely. In addition, this chemical is not found to be exhibit acute dermal toxicity. Thus, this end point was not considered for testing.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
NOAEL was 1000 ppm (50 mg/kg/day) & LOAEL was considered to be 3000 ppm (150 mg/kg/day) when F344/ N male and female rats were treated with 2-Biphenylamine.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The chemical biphenyl-2-ylamine has low vapour pressure of 0.000117 mm Hg at 25oC as well as particle size that are larger than the inhalable particulates. In addiiton, the use fo the chemical does not indicate the likelyihood of epeated exposure by the inhalation route. Thus, this end point was considered for waiver since the chemical is not expected to exhibit adverse effects by the repeated inhaltion route of exposure.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The chemical 2-Biphenylamine finds use in manufacture of fine chemicals and formulation of preparations. Thus, the repeated exposure by the dermal route is unlikely. In addition, this chemical is not found to be exhibit acute dermal toxicity. Thus, this end point was not considered for testing.

Justification for classification or non-classification

On the basis of available information, the substance is not likely to exhibit toxic effects on repeated exposure by the oral, inhalation and dermal route within the dose levels mentioned in the studies.

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