Registration Dossier

Administrative data

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is not a guideline study, but it is considered a klimisch 2e study as it is well documented, meets generally accepted scientific principles and is acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Carcinogenicity of p-Chloro-benzotrichloride
Author:
Fukuda K., Matsushita S. and Takemoto K.
Year:
1979
Bibliographic source:
Proceedings of the Japan Association of Industrial Health, 330-331

Materials and methods

Principles of method if other than guideline:
Repeated dose exposure via gavage with afterwards an observation period. At the end of this post exposure period animals were autopsied and examined for histopathological changes.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): p-chlorbenzotrichlorid

No more data available

Test animals

Species:
mouse
Strain:
ICR
Sex:
female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1 mL sesame oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
17.5 weeks
Frequency of treatment:
twice a week
Post exposure period:
14 months
Doses / concentrations
Remarks:
Doses / Concentrations:
0.05, 0.13, 0.32, 0.8, 2 µL
Basis:
actual ingested
No. of animals per sex per dose:
See table in results section
Control animals:
yes

Results and discussion

Results of examinations

Relevance of carcinogenic effects / potential:
Intragestric administration of 4-chloro-benzotrichloride produced stomach cancer as well as a wide variety of tumors such as lung cancers, malignant lymphoma and thymoma in a dose responsive manner in female ICR mice. Histopathological changes were thouroughly investigated to reveal tumors appearances.

Any other information on results incl. tables

Table giving a detailed view of the observed tumors.

Dose (µL)

Initial number of animals

Effectivenumber of animals

Forestomach

Glandular stomach carcinoma

Lung

Malignant lymphomas

Thymoma

Skin tumor

Other tumors

Number of mice with tumor(s)

50% mortality reached after (months)

Squamous cell carcinoma

Carcinoma in situ

Multiple papilloma

Adenocarcinoma

Multiple adenoma

Malignant

Benign

Total

 

0

30

26

 

 

 

 

 

1

1

 

 

 

1

1

2/26

 

0.05

30

22

 

 

2

1

3

2

 

 

 

 

4

2

6/22

> 18

0.13

30

28

 

 

4

 

7

1

1

 

 

1

8

2

10/28

> 18

0.32

26

22

 

1

5

 

10

6

 

 

1

1

10

7

17/22

> 18

0.8

31

29

6

4

2

 

15

10

 

4

2

3

20

7

27/29

12.3

2

31

29

7

3

1

 

2

17

5

8

6

1

16

9

25/29

4.7

- Tumors developed earliest in mice exposed to the highest dose

- Malignant lymphoma and thymoma:

11/29 (38%) mice exposed to 2µL and 3/29 (10%) mice exposed to 0.8µL had malignant lymphoma and thymoma

- Stomach cancer:

Approximately 5 months after first application of test substance stomach cancers begon to develop. Cumulative index was less than 25% in each group (exclusion of carcinoma in situ).

With the exception of a single differentiated tubular adenocarcinoma in the low dose group, all were epidermoid carcinomas.

- Lung cancers:

Both adenocarcinomas and adenomas were seen in all dose groups with the greatest number (25/31) in the group receiving 0.8 µL

- Skin cancers (squamous cell carcinomas, sarcomas and adenocarcinomas), mammary cancer and salivary gland cancer were also seen in the highest dose groups.

- Total number of mice with tumors was 6/22, 10/28, 17/22, 27/29 and 25/29 for the doses 0.05, 0.13, 0.32, 0.8 and 2 µL respectively. Hence, the development of tumors happened in a dose responsive manner.

- In the control group 2 mice out of 26 had tumor

Applicant's summary and conclusion

Conclusions:
The authors tested the carcinogenicity of 4-chloro-benzotrichloride using a repeated dose methodology exposing female ICR mice to the test substance via gavage. Under the test conditions, a high incidence of lung tumors and also stomach cancers, skin cancers, mammary cancer, salivary gland cancer and malignant lymphoma and thymoma were observed at the end of the experiment. These cancers developed in a dose responsive manner.
Executive summary:

The authors tested the carcinogenicity of 4-chloro-benzotrichloride (CAS n° 5216-25-1) using a repeated dose methodology exposing female ICR mice to the test substance via oral gavage. The animals were exposed twice a week for 17.5 weeks to 0.05, 0.13, 0.32, 0.8 and 2 µL of the test substance in 1mL of sesame oil. Afterwards the animals were observed for another 14 months. Also control animals were included in the experiment and at the end of the experiment all animals were autopsied and examined for histopathological changes.

Under the test conditions, tumors generally developed earliest in mice exposed to the highest dose. A high incidence of lung tumors and also stomach cancers, skin cancers (squamous cell carcinomas, sarcomas and adenocarcinomas), mammary cancer, salivary gland cancer and malignant lymphoma and thymoma were observed at the end of the experiment especially in the high dose groups. In mice with lung cancer both adenocarcinomas and adenomas were seen in all dose groups with the greatest number (25/31) in the group receiving 0.8 µL of the test substance. Approximately 5 months after first application of the test substance stomach cancers began to develop. The cumulative index of all stomach cancers was less than 25% in each group (exclusion of carcinoma in situ). With the exception of a single differentiated tubular adenocarcinoma in the low dose group, all were epidermoid carcinomas. Furthermore, 11/29 (38%) mice exposed to 2 µL and 3/29 (10%) mice exposed to 0.8µL had malignant lymphoma and thymoma. In the control group only 2 mice out of 26 had tumors whereas the total number of mice with tumors was 6/22, 10/28, 17/22, 27/29 and 25/29 for the doses 0.05, 0.13, 0.32, 0.8 and 2 µL respectively. Hence, the development of tumors happened in a dose responsive manner.

The GLP status of the study is unknown. The study is however sufficiently documented, meets generally accepted scientific principles and is acceptable for assessment. Thus it should be considered reliable with restrictions, Klimisch 2e.