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Toxicological information

Carcinogenicity

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Description of key information

 non carcinogenic NOAEL was considered to be 110 mg/kg bw/day when Fischer 344 male rats were treated with 2-Nitro-p-phenylenediamine orally in feed for 78 weeks. 

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:
key study
Reliability:
2 (reliable with restrictions)
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Carcinogen toxicity conducted on Fischer 344 male rat
GLP compliance:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Source: A. R. Schmidt, Madison, Wisconsin, and LaboratorySupply Company, Inc., Indianapolis, Indiana.Age at study initiation:6 weeks oldWeight at study initiation: No dataFasting period before study: Housing: polycarbonate cages suspended from aluminum racks. Ab-sorb-dri® hardwoodchip beddingDiet (e.g. ad libitum): Wayne Lab-Blox meal, ad libitum Water (e.g. ad libitum): Acidulated water (pH 2.5) was supplied to animals in water bottles filled by an automated metering device, ad libitumAcclimation period: quarantined for 2 weeks prior to initiationENVIRONMENTAL CONDITIONSTemperature (°C): 22° to 26°CHumidity (%): 45 and 55 percentAir changes (per hr): Incomingair was filtered through HEPA filters, at a rate of 12 to 15 complete changes of room air per hour. Photoperiod (hrs dark / hrs light):Fluorescent lighting was provided 8 hours per day (9:00 a.m. to 5:00 p.m.).
Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: basal laboratory diet
Details on exposure:
DIET PREPARATIONThe chemical was removed from its container and a proper amount was blended with an aliquot of the ground feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical verification of doses or concentrationSpectrophotometrically
Duration of treatment / exposure:
78 weeks treatment
Frequency of treatment:
daily
Post exposure period:
27 weeks observation
Remarks:
Doses / Concentrations:27.5mg/kgbw and 55 mg/kgbwBasis:
No. of animals per sex per dose:
50 male rats /dose group
Control animals:
yes
Details on study design:
Dose selection rationale:To establish the maximum tolerated concentrations of 2-nitro-p- phenylenediamine for administration to dosed animals in the chronic studies, subchronic toxicity tests were conducted with 5 male rats/ dose group.No abnormal clinical signs were recorded for any rat group. The high concentration selected for administration to dosed male rats in the chronic bioassay was 55mg/kgbw
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes / No / No data: No data Time schedule: No dataCage side observations checked in table [No.?] were included.: No dataDETAILED CLINICAL OBSERVATIONS: Yes / No / No data: YesTime schedule: No dataBODY WEIGHT: Yes / No / No data: YesTime schedule for examinations:once a week for the first 6 weeks, every 2 weeks for the next 12 weeks, and at monthly intervals thereafterFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): YesFood consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data: Food consumption data were collected at monthly intervals from 20% of the animals in each group.Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No dataFOOD 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: Yes / No / No data: No dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data: No dataTime schedule for examinations:No dataOPHTHALMOSCOPIC EXAMINATION: Yes / No / No data: No dataHAEMATOLOGY: Yes / No / No data: No dataCLINICAL CHEMISTRY: Yes / No / No data: No dataURINALYSIS: Yes / No / No dataNo dataNEUROBEHAVIOURAL EXAMINATION: Yes / No / No data: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table) / No / No data: YesHISTOPATHOLOGY: Yes (see table) / No / No data: Yes
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):
effects observed, treatment-related
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
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY:No other abnormal clinical signs were recorded. The Tarone’s test for association between dosage and mortality was not significant for males.BODY WEIGHT AND WEIGHT GAIN:Dose-related mean body weight depression was apparent in male rats from week 12 until week 87FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No dataFOOD EFFICIENCY: No dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):No dataOPHTHALMOSCOPIC EXAMINATION:HAEMATOLOGY: No data CLINICAL CHEMISTRY: No dataURINALYSIS: No dataNEUROBEHAVIOUR: No dataORGAN WEIGHTS: No dataGROSS PATHOLOGY:There were adequate numbers of male rats at risk from late developing tumors as 94 percent (47/50) of the high dose, 92 percent (46/50) of the low dose, and 80 percent (16/20) of the controls survived on test until the termination of the study.HISTOPATHOLOGY: NON-NEOPLASTIC:There was also a variety of nonneoplastic lesions in both control and dosed animals. Such lesions have been encountered previously as spontaneous occurrences in laboratory ratsHISTOPATHOLOGY: NEOPLASTIC (if applicable):A variety of neoplasms was seen in both control and dosed rats.Each type of tumor represented had been encountered previously as a spontaneous lesion in rats. HISTORICAL CONTROL DATA (if applicable):No dataOTHER FINDINGS: Statistical analysis of the results :For male rats, the Cochran-Armitage test indicated a significant (p = 0.017) positive association between dose and the combined 1ncidence of C-cell carcinomas or C-cell adenomas of the thyroid. However, the Fisher exact tests comparing high dose to control and low dose to control were not significant. For male rats there was the possibility of a negative association between dose and the combined incidence of leukemia or malignant lymphoma as the Cochran-Armitage test and the Fisher exact tests indicated significant negative results.The theoretical possibility of tumor induction in rats by 2-nitro-p-phenylenediamine could not be established under the conditions of this test.
Dose descriptor:
NOAEL
Effect level:
110 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No carcinogenic effect on Testis
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Conclusions:
Non carcinogenic NOAEL was considered to be 110 mg/kg bw/day when Fischer 344 male rats were treated with 2-Nitro-p-phenylenediamine orally in feed for 78 weeks.
Executive summary:

In a Chronic carcinogenicity test, Fischer 344 male rats were treated by using 2-Nitro-p-phenylenediamine in the concentration of 0, 55 and 110 mg/kg bw/day for male orally in diet. No significant effect on survival and clinical sign of treated male rats were observed as compared to control. Decrease in body weight was observed in treated male rats throughout study as compared to control. Nonneoplastic and neoplastic such as Leukemia or Malignant Lymphoma of Hematopoietic System, C-Cell Carcinoma or C-Cell Adenoma of Thyroid, Islet-Cell Adenoma of Pancreatic Islets and Interstitial-Cell Tumor of Testis were observed in treated male rats. But, the observed Nonneoplastic and neoplastic lesion are considered to represent spontaneous lesions in these animals. Therefore, non carcinogenic NOAEL was considered to be 110 mg/kg bw/day when Fischer 344 male rats were treated with 2-Nitro-p-phenylenediamine orally in feed for 78 weeks.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
110 ng/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is of K1 and from peer reviewed publication

Additional information

In a study conducted by U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE (1979), carcinogenicity was evaluated in Fischer 344 male rats by using 2-Nitro-p-phenylenediamine in the concentration of 0, 55 and 110 mg/kg bw/day for male orally in diet. No significant effect on survival and clinical sign of treated male rats were observed as compared to control. Decrease in body weight was observed in treated male rats throughout study as compared to control. Nonneoplastic and neoplastic such as Leukemia or Malignant Lymphoma of Hematopoietic System, C-Cell Carcinoma or C-Cell Adenoma of Thyroid, Islet-Cell Adenoma of Pancreatic Islets and Interstitial-Cell Tumor of Testis were observed in treated male rats. But, the observed Nonneoplastic and neoplastic lesion are considered to represent spontaneous lesions in these animals. Therefore, non carcinogenic NOAEL was considered to be 110 mg/kg bw/day when Fischer 344 male rats were treated with 2-Nitro-p-phenylenediamine orally in feed for 78 weeks.

In the above similar study, carcinogenicity was evaluated in Fischer 344 female rats by using 2-Nitro-p-phenylenediamine in the concentration of 0, 110 and 220 mg/kg bw/day for female orally in diet. No significant effect on survival and clinical sign of treated male rats were observed as compared to control. Decrease in body weight was observed in treated male rats throughout study as compared to control. Nonneoplastic and neoplastic such as Leukemia or Malignant Lymphoma of Hematopoietic System, Chromophobe Adenoma of Pituitary and Endometrial Stromal Polyp of Uterus were observed in treated female rats. But, the observed Nonneoplastic and neoplastic lesion are considered to represent spontaneous lesions in these animals. Therefore, non carcinogenic NOAEL was considered to be 220 mg/kg bw/day when Fischer 344 male rats were treated with 2-Nitro-p-phenylenediamine orally in feed for 78 weeks.

In the above similar study, carcinogenicity was evaluated in B6C3FI male and female mice using 2-Nitro-p-phenylenediamine in the concentration of 0, 330 and 660 mg/kg bw/day in diet. No significant effect on survival and clinical sign of treated male and female mice were observed as compared to control. Decrease in body weight was observed in treated male and female mice throughout study as compared to control. Alveolar/Bronchiolar Adenoma of Lung, Leukemia orMalignant Lymphoma of Hematopoietic System and Hepatocellular Carcinoma or Hepatocellular Adenoma were observed in male mice at 330 and 660 mg/kg bw/day, but tumors were of the usual types and in the usual incidences seen in aging B6C3Fl male mice. In female mice, Hepatocellular adenoma and hepatocellular carcinoma were observed both at 330 and 660 mg/kg bw/day as compared to control. Therefore, Non carcinogenic NOAEL for male mice was considered to be 660 mg/kg bw/day and carcinogenic LOAEL for female mice was 330 mg/kg bw/day when B6C3FI male and female mice were treated with 2-Nitro-p-phenylenediamine orally in diet. Thus, based on the above available data, 2-Nitro-p-phenylenediamine (CAS no 5307-14-2) as per CLP regulation likely to be non hazardus

Justification for classification or non-classification

2-Nitro-p-phenylenediamine (CAS no 5307-14-2) as per CLP regulation likely to be non hazardus