Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: oral, other
Remarks:
Combined repeated dose & carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication

Data source

Reference
Reference Type:
review article or handbook
Title:
Discrimination of Carcinogens by Hepatic Transcript Profiling in Rats Following 28-day administration
Author:
Hiroshi Matsumoto, Yoshikuni Yakabe, Koichi Saito, Kayo Sumida, Masaru Sekijima, Koji Nakayama, Hideki Miyaura, Fumiyo Saito, Masanori Otsuka and Tomoyuki Shirai
Year:
2009
Bibliographic source:
Cancer Informatics 2009:7 253–269

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of 2-Chloro-p-phenylenediamine SO4
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material: 2-chlorobenzene-1,4-diammonium sulphate
- IUPAC name: 2-chlorobenzene-1,4-diammonium sulphate
- Molecular formula: C6H7ClN2.xH2O4S
- Molecular weight: 240.6661 g/mole
- Smiles : S(=O)(=O)(O)O.c1(c(ccc(c1)N)N)Cl
- Inchl: 1S/C6H7ClN2.H2O4S/c7-5-3-4(8)1-2-6(5)9;1-5(2,3)4/h1-3H,8-9H2;(H2,1,2,3,4)
- Substance type: Organic
- Physical state: Solid (Light grey powder)
Specific details on test material used for the study:
- Name of test material : 2-Chloro-p-phenylenediamine SO4
- Molecular formula : C6H7ClN2xH2O4S
- Molecular weight : 240.6661 g/mol
- Substance type: Organic
- Physical state: No data
- Impurities (identity and concentrations): No data

Test animals

Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
No data
Sex:
male
Details on test animals and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
(Atsugi, Japan)
- Age at study initiation: 6 weeks
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): pelleted chow food (CRF-1, Oriental Yeast, Co., Ltd) ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data

Oral: gavage
1% CMC
Details on oral exposure
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with No data at dose levels of 0 or 100 mg/Kg/day

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): No data
- Concentration in vehicle: 0 or 100 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1%
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with No data at dose levels of 0 or 100 mg/Kg/day

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): No data
- Concentration in vehicle: 0 or 100 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once a day
Doses / concentrations
Remarks:
0 or 100 mg/Kg/day
No. of animals per sex per dose:
Total: 8
0 mg/Kg/day: 4 male rats
100 mg/Kg/day: 4 male rats
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The administration dose for each chemical was set around their minimum carcinogenic doses for carcinogens or maximum tolerable doses based on the information in NTP and CCRIS database as well as other literatures for non-carcinogens.
- Rationale for animal assignment (if not random): No data
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: No data
- Time schedule for examinations: No data

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 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 averages 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: No data
- 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: 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

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, Rats were humanly sacrificed with CO2-O2 (4:1) gas inhalation at 3, 14 or 28 days after administration. The livers were immediately excised and weighed

HISTOPATHOLOGY: Yes, A portion of the left lateral lobe was also taken for histopathology. Tissues were fixed in 10% neutral-buffered formalin, and subsequently sectioned and stained with hematoxylin and eosin.
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No histological abnormalities were noted
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
100 other: mg/Kg/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No significant alterations were noted at the mentioned dose level

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse Effect Level (NOAEL) for 2-Chloro-p-phenylenediamine SO4 is considered to be 100 mg/kg/day.
Executive summary:

Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of 2-Chloro-p-phenylenediamine SO4. The study was performed using 6 week old male F344 rats in a 28 days study. The test chemical was mixed with 1% CMC and used at dose level of 0 or 100 mg/Kg/day.Rats were humanly sacrificed with CO2-O2 (4:1) gas inhalation at 3, 14 or 28 days after administration. The livers were immediately excised and weighed. Tissues were fixed in 10% neutral-buffered formalin, and subsequently sectioned and stained with hematoxylin and eosin.No histological abnormalities were noted due to test chemical treatment. The No Observed Adverse Effect Level (NOAEL) for 2-Chloro-p-phenylenediamine SO4 is considered to be 100 mg/kg/day.