Biphenyl-2-ylamine

Carcinogenicity

Description of key information

The Low Observed Adverse Effect Level (LOAEL) in male/female F344/N rats is found to be 10000 ppm (500 mg/Kg bw/day) while the NOAEL was reported to be 150 mg/kg bw/day.
Administration of 2-biphenylamine resulted in the formation of erythroid hyperplasia and transitional cell hyperplasia in male and female rats. Hyperplasia is defined as the enlargement of an organ or tissue caused by an increase in the reproduction rate of its cells, often as an initial stage in the development of cancer. Thus, the chemical is likely to be a suspected human carcinogen which is in line with the Harmonized classification of Carcinogen Category 2 within the CLP regulation. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: 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 peer reviewed journal

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

13 week chronic study was conducted to evaluate the carcinogenic effects of 2-Biphenylamine on Mice.

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

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 old

- Weight at study initiation: No data available

- Housing: Five per cage in polycarbonate cages and covered with nonwoven polyester filter sheets containing Aspen Bed and Beta chips

- Diet: ad libitum Wayne Lab Blox® meal, Allied Mills, Inc. (Chicago, IL). ad libitum

- Water: ad libitum - Tap water via Edstrom Automatic Watering System, Edstrom Industries (Waterford, WI)
- Acclimation period:1 week
ENVIRONMENTAL CONDITIONS
Temperature: 17.2°-32.2°C.
- Humidity (%): Humidity uncontrolled.
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): Fluorescent lighting provided 12 hours per day.

Route of administration:

oral: feed

Vehicle:

other: Diet

Details on exposure:

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): Wayne Lab Blox® feed

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis was performed by vapor-phase chromatographic method

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, 50, 166.7, 500, 1666.7 and 5000 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:

- 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.

Positive control:

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, Weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the completion of 1, 4, and 13 weeks of chemical administration
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: All animals
- Parameters checked in table [No.?] were examined. White cell count, hemoglobin, red blood cell count, hematocrit, neutrophils and differential leucocyte
counts

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
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 VonKossa, Mallory trichrome, MacManus-PAS, or Prussian blue solutions.

Tissues examined included: 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.

Other examinations:

Tissues examined included: 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.

Statistics:

For the hematology data, Jonckeere'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:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

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:

effects observed, treatment-related

Description (incidence and severity):

HAEMATOLOGY Significant (P < 0.001) dose-related decreases in hemoglobin concentration and red blood cells were observed in both male and female rats examined at weeks 1,4, and 13.

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Splenic enlargement was noted in male and female mice fed 30000 ppm

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Splenomegaly was observed in all rats fed 30,000 ppm and in 8/10 males and 2/ 10 females fed 10,000 ppm.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Erythroid hyperplasia in bone marrow was seen in 10/ 10 females and 9/10 males receiving 30,000 ppm and in 9/10 females and 7/10 males receiving 10,000 ppm.

Details on results:

MORTALITY: One male rat from the group receiving 300 ppm and five female rats receiving 30,000 ppm died on day 26. All five females were from the same cage and were found dead on the same day, suggesting that the deaths were not chemical-related.

BODY WEIGHT AND WEIGHT GAIN- compound-related depression in the mean body weight gains was observed. The maximum depression in body weight gain relative to controls
was observed at 30,000 ppm, amounting to 47.6% for males and 38.9% for females

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Test material provided through oral feed resulting in the formation of hyperplasia

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed at this dose

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

HAEMATOLOGY

Significant (P < 0.001) dose-related decreases in hemoglobin concentration and red blood cells were observed in both male and female rats examined at weeks 1,4, and 13. Leucocyte count was markedly (P < 0.001) increased in both

male and female rats at weeks 1 and 4, but this trend had diminished by week 13. This diminishing trend in leucocyte count with time may be due to activation of a hemeostatic mechanism in these animals. Hematocrit levels showed no consistent effect, although there was some evidence of a dose-related decrease in female rats at week 1 (P < 0.05) and week 13 (P<0.001).

HISTOPATHOLOGY: NON-NEOPLASTIC

Splenomegaly was observed in all rats fed 30,000 ppm and in 8/10 males and 2/ 10 females fed 10,000 ppm. Hemosiderosis, congestion, and extramedullary hematopoiesis were found in the spleens of 9/10 or 10110 of each group of rats receiving 3,000 ppm or more and in females receiving 1,000 ppm or more of 2-biphenylamine.

Renal effects in rats receiving 30,000 ppm technical-grade 2-biphenylamine included cystic tubular degeneration and papillary necrosis (9/10 or 10/ 10 rats of each sex), interstitial fibrosis (all males and 4/10 females), and chronic nephritis (all males and 4110 females).

 

 

Conclusions:

The Low Observed Adverse Effect Level (LOAEL) in male/female F344/N rats is found to be 10000 ppm (500 mg/Kg bw/day) while the NOAEL was reported to be 150 mg/kg bw/day

Executive summary:

The chronic carcinogenicity study was conducted with 2-biphenylamine by feeding diets containing 00, 300, 1,000, 3,000, 10,000 and 30,000 ppm (0, 15, 50, 150, 500 and 1500 mg/kg/day) test compound to groups of 10/10 male/female F344/N rats for 13 weeks. Groups of 10 rats of each sex served as controls.

 Administration of 2-biphenylamine resulted in the formation of erythroid hyperplasia and transitional cell hyperplasia in male and female rats.

The Low Observed Adverse Effect Level (LOAEL) in male/female F344/N rats is found to be 10000 ppm (500 mg/Kg bw/day) while the NOAEL was reported to be 150 mg/kg bw/day

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from peer reviewed journal.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Studies for carcinogenicity from reliable sources having Klimisch rating 2 were reviewed for the target and read across chemical

The summary of the results are presented below:

Sr. No	End point	Value	Species	Route	Effects	Remarks
1	NOAEL	166.7 mg/kg bw/d	Mouse	Oral	No adverse effects due to the test chemical	Experimental data for target CAS 90-41-5
2	LOAEL	500mg/kg bw/d	Mouse	Oral	Test material provided through oral feed resulting in the formation of hyperplasia	Experimental data for target CAS 90-41-5
3	NOAEL	150 mg/kg bw/d	Rat	Oral	No adverse effects due to the test chemical	Experimental data for target CAS 90-41-5
4	LOAEL	500 mg/kg bw/d	Rat	Oral	Test material provided through oral feed resulting in the formation of hyperplasia	Experimental data for target CAS 90-41-5
5	LOAEL	50 mg/ kg bw/ d	Mouse	Oral: feed	Neoplastic in females and ambiguous results in males.	Experimental data for RA CAS: 2185-92-4
6	NOEL	150 mg/ kg bw/ d	Rat	Oral: feed	Clinical signs, body weight, mortality and carcinogenic effects if any observed in control and dosed rats	Experimental data for RA CAS: 2185-92-4

 

Based on the studies summarized in the above table it can be observed that the read across substance is found to be carcinogenic in female mice whereas it is non-carcinogenic in rats and male mice.

Justification for selection of carcinogenicity via oral route endpoint:
The Low Observed Adverse Effect Level (LOAEL) in male/female F344/N rats is found to be 10000 ppm (500 mg/Kg bw/day) while the NOAEL was reported to be 150 mg/kg bw/day.
Administration of 2-biphenylamine resulted in the formation of erythroid hyperplasia and transitional cell hyperplasia in male and female rats.