Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
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 publication

Data source

Reference
Reference Type:
publication
Title:
Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model
Author:
R.R. Maronpot, K. Mitsumori , P. Mann , M. Takaoka , S. Yamamoto , T. Usui , H. Okamiya , S. Nishikawa, T. Nomura
Year:
2000
Bibliographic source:
Toxicology 146 (2000) 149–159

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
Details of guidelines not mentioned in publication.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
CAS No: 104-94-9
Chemical Name: 4-methoxyaniline (Synonym: p-anisidine)
Nature of chemical: Organic

Test animals

Species:
mouse
Strain:
CB6F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Central Institute for Experimental Animals (Kawasaki, Japan)
- Age at study initiation:≈6 week old
- Weight at study initiation: No data available
Housing: housed in polycarbonate cages (singly housed for males and 5:cage
for females) with absorbent hardwood bedding
- Diet (e.g. ad libitum): NIH-07 open formula diet (ad libitum)
- Water (e.g. ad libitum): (ad libitum)
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): continuous temperature monitoring.
- Humidity (%): continuous humidity monitoring.
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-h light:12-h dark cycle

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Feed
Details on oral exposure:
Rate of preparation of diet (frequency): p-Anisidine admixed with feed at concentrations of 0.450 and 0.225%
- Mixing appropriate amounts with (Type of food): NIH-07 open formula diet
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
18 months
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
321.428 And 642.857 mg/kg (0.225 and 0.450%)
Basis:
nominal in diet
No. of animals per sex per dose:
60 animal/sex/dose
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data available
Statistics:
No data available

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs: No clinical sighs observed in animals during study. Mortality: all animals were necropsied
Mortality:
mortality observed, treatment-related
Description (incidence):
Clinical signs: No clinical sighs observed in animals during study. Mortality: all animals were necropsied
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In male decrease in body weight and in female only in low dose mice decrease in body weight observed.
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
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Gross lesions included dark red spleens and small lung nodules in a few mice.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
no significant dose-related trends for either pulmonary or splenic tumors
Details on results:
In a combined repeated dose & carcinogenicity study using the test chemical p- anisidine the No Observed Adverse Effect Level (NOAEL) was found tobe at 642.857 mg/kg concentration of p-anisidine administered daily over an 18 month period.

Effect levels

Dose descriptor:
NOAEL
Effect level:
642.857 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Gross pathology and histopathology evaluations

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a combined repeated dose & carcinogenicity study using the test chemical p- anisidine the No Observed Adverse Effect Level (NOAEL) was found tobe at 642.857 mg/kg concentration of p-anisidine administered daily over an 18 month period.
Executive summary:

Repeated dose toxicity test was performed on CB6F1 males and female at two different laboratories in Japan and USA. p-anisidine was mixed with feed and given to animals at two different concentrations as 321.428 and 642.857 mg/kg and observed for 18 months. After 18 months all mice were necropsied and observed histopathologically. Standard hematoxylin and Eosin-stained slides were also evaluated.

 

After 18 months no clinical effects were observed in male and female mice. Decrease in body weight in males and some females of low dose concentration were also observed. On gross pathology dark red spleens and small lung nodules in a few mice and no significant dose-related trends for either pulmonary or splenic tumors were observed. Some effects were also observed in control also.

 

So on the basis of above experimental results it was concluded that the No Observed Adverse Effect Level (NOAEL) at 642.857 mg/kg concentration of p-anisidine