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Toxicological information

Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Experimental neoplasia in rats from oral administration of 3,3'-dichlorobenzidine, 4,4'-methylene-bis- (2-chloroaniline), and 4,4'-methylene-bis(2-methylaniline)
Author:
Stula EF, Sherman H, Zapp JA Jr, Clayton JW Jr
Year:
1975
Bibliographic source:
Toxicol Appl Pharmacol 31: 159-176

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 4,4'-Methylene-bis (2-methylaniline) (Me-MDA)
- Analytical purity: not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: ChR-CD rats (Charles River Cesarean Derived, Sprague-Dawley origin, barrier sustained, random bred albino)
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Age at study initiation: 38 days
- Housing: The rats were housed two to a suspended stainless-steel cage in an air-conditioned room
- Diet (ad libitum): Standard diet of ground Purina Laboratory Chow containing 1% added corn oil
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
Artificial lighting of the room was for 8 hr of each day.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Average exposure period for males 388 days and for females 482 days
Six rats per group were sacrificed after 1 year on test for an interim evaluation
Frequency of treatment:
continously, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
200 ppm
Basis:
actual ingested
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
No analysis of clinical chemisty and hematology was performed. Data on body weight changes and organ weights were not given.
Sacrifice and pathology:
A necropsy was performed on all rats, and a set of 30 organs was sampled for histologic examination even if there was no gross evidence of tumor formation. Rats found moribund were sacrificed in order to obtain satisfactory tissue sections. Six rats per group were sacrificed after 1 year on test for an interim evaluation. When a group size was reduced to six rats, a terminal sacrifice was conducted on that group. When a rat had multiple primary tumors of one histologic type, they were counted as one tumor.
Statistics:
The chi-square method was used for a statistical analysis of the tumor incidence data.

Results and discussion

Any other information on results incl. tables

A terminal sacrifice on male rats of the treatment group was conducted after 16 months, whereas the females were terminated after 19 months. Average exposure period of the control group for males and females was reported to be 564 days (range: 63-731 days) and 628 days (range: 306-733), respectively. Average exposure period of animals treated with the test substance for males and females was reported be 388 days (range: 109-481 days) and 482 days (range: 259-580 days), respectively.

 

Number of animals evaluated for tumor formation was 44, since the 6 animals sacrificed after 1 year were excluded. Data on body weight changes and organ weights were not given.

 

Liver tumors observed in both sexes consisting in hepatocellular ademoma (M, F 6/44; control 0/44 each), hepataocellular carcinoma (M 8/44; F 19/44; control 0/44 each) and cholangiocarcinoma (F 2/44) were statistically significant from control group. Furthermore, males treated with the test substance showed statistically significant increase in skin fibroma (13/44; control 2/44) and mammary fibroadenoma (14/44; control 1/44).

 

Nonneoplastic liver changes from exposure to the test substance were reported as hepatocytomegaly, fatty change, necrosis, bile duct proliferation, and fibrosis.

Applicant's summary and conclusion