α,α,α-trichlorotoluene

Carcinogenicity

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

Test material information

Constituent 1

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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.0315, 0.125, 0.5, 2.0 µL
Basis:
actual ingested

Doses / concentrations 2

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		1/39^a	2/39^b	3/39^c	5/40^d	4/38^e

^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.