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Toxicological information

Carcinogenicity

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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 well described, only few details are lacking concerning clinical signs. Thus as the study is well documented, meets generally accepted scientific principles and is acceptable for assessment it is considered a Klimisch 2e

Data source

Reference
Reference Type:
publication
Title:
Carcinogenicity of benzotrichloride administered to mice by gastric intubation
Author:
Fukuda K., Matsushita H., Takemoto K. and Toya T.
Year:
1993
Bibliographic source:
Industrial Health, 31: 127-131

Materials and methods

Principles of method if other than guideline:
Carcinogenicity after repeated oral treatment (duration 25 weeks, 2 times/week)
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
α,α,α-trichlorotoluene
EC Number:
202-634-5
EC Name:
α,α,α-trichlorotoluene
Cas Number:
98-07-7
Molecular formula:
C7H5Cl3
IUPAC Name:
α,α,α-trichlorotoluene
Constituent 2
Reference substance name:
trichloromethylbenzene
IUPAC Name:
trichloromethylbenzene
Details on test material:
- Name of test material (as cited in study report): benzotrichloride (BTC)
- Analytical purity: 99.5%
- Other:
Supplier: Tokyo Kasei Co. Ltd., Tokyo

No more data available

Test animals

Species:
mouse
Strain:
ICR
Sex:
female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
25 weeks
Frequency of treatment:
twice a week
Post exposure period:
experiment terminated at the 18th month after start of exposure
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.0315, 0.125, 0.5, 2.0 µL
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0.043, 0.17, 0.7, or 2.7 mg
Basis:
actual ingested
No. of animals per sex per dose:
40 animals/dose group
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Relevance of carcinogenic effects / potential:
Mice were exposed repeatedly at low doses and histopathological changes were investigated after a long period. Development of dose-related malignant tumours: squamous-cell carcinomas and papillomas of the forestomach, adenocarcinomas and adenomas in the lung and thymic lymphosarcoma and lymphatic leukemia of the haematopoietic system.

Any other information on results incl. tables

- Mortality:

increased dose-dependently (mice exposed to the highest dose died earlier than those in the other dose groups)

mostly due to lymphosarcoma and stomach cancer.

- Table showing the time (months) at which 50% mortality (LD50) was reached in the different dose groups (not taken into account the control group). Furthermore the number of mice with tumor are given as well as the type.

 

Control

0.0315 µL

0.125 µL

0.5 µL

2.0 µL

 

Control

0.043 mg

0.17 mg

0.7 mg

2.7 mg

LD50 (month)

 

>18

>18

16.5

6.5

Number of mice with tumor / effective number of mice (%)

4/39 (10)

10/39 (26)

30/39 (77)*

39/40 (98)*

36/38 (95)*

Number of mice with tumor

Forestomach

Squamous cell carcinoma

0/39

0/39

2/39

21/40

24/38

Papilloma

0/39

0/39

0/39

2/40

1/38

%

0

0

5

58*

66*

Lung

Adenoma

1/39

6/39

17/39

19/40

14/38

Adenocarcinoma

1/39

1/39

9/39

16/40

10/38

%

5

18

67*

88*

63*

Haematopoietic system (%)

1/39 (3)

2/39 (5)

1/39 (3)

3/40 (8)

8/38 (21)*

Others

1/39a

2/39b

3/39c

5/40d

4/38e

aFibrosarcoma of the uterus

b1 hemangioendothelioma of the liver and 1 adenocarcinoma of the Harderian gland

c1 adenocarcinoma of the salivary gland and 1 adenocarcinoma and 1 adenoma of the mammary gland

d1 squamous cell carcinoma of the oesophagus, 1 carcinosarcoma and 1 adenocarcinoma of the salivary gland, and 1 adenocarcinoma and 1 adenoma of the mammary gland

e1 adenocarcinoma of the salivary gland, and 1 adenosquamous cell carcinoma, 1 adenocarcinoma and 1 adenoma of the mammary gland

*Significantly different from the control (p<0.01) (Fisher’s exact probability test)

Applicant's summary and conclusion

Conclusions:
The authors tested the carcenoginicity of benzotrichloride after repeated oral treatment (duration 25 weeks, 2 times/week). In these conditions mortality of the treated mice increased dose-dependently and was mostly due to lymphosarcoma and stomach cancer. Furthermore, dose-related malignant tumours developed: squamous-cell carcinomas and papillomas of the forestomach, adenocarcinomas and adenomas in the lung and thymic lymphosarcoma and lymphatic leukemia of the haematopoietic system.
Executive summary:

The authors tested the carcenoginicity of benzotrichloride (CAS n° 98-07-7) after repeated oral treatment (duration 25 weeks, 2 times/week). Female mice (ICR strain) were administered by oral gavage the following amounts of test substance: 0.00315, 0.125, 0.5 and 2 µL (40 animals/dose group) and a control was also added.

The test substance was administered twice a week during 25 weeks. At month 18 (from start of the exposure experiment) all animals were killed, except for the mice in the highest dose group which were killed at the 12th month, and examined histologically . After gross observation, organs and tumors were dissected and stainings were used when needed.

Hence, in the test conditions, mortality of the treated mice increased dose-dependently. Moreover, the mice at the highest dose concentration showed high mortality at 12 months (i.e. 95%) and the surviving mice were in poor condition. Hence for these dose group the animals were already killed at 12 months. Furthermore, benzotrichloride induced local carcinogenesis in the stomach, especially forestomach (two highest dose levels showed significantly more mice with tumor than control). A significant increase in the number of animals with lung tumors was observed in comparison with the control for all dose levels except 0.0315 µL.

Thus, dose-related malignant tumours were developed: squamous-cell carcinomas and papillomas of the forestomach, adenocarcinomas and adenomas in the lung and thymic lymphosarcoma and lymphatic leukemia of the haematopoietic system.

No data was availalbe concerning the GLP status of this study. As this study is well described with only few details lacking concerning clinical signs it is considered a Klimisch 2e.