α-chlorotoluene

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: dermal

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 fulfils general scientific criteria. Thus we consider this study a klimisch 2e as it is well documented, meets generally accepted scientific principles and is acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Carcinogenicity of benzyl chloride, benzal chloride, benzotrichloride and benzoyl chloride in mice by skin application

Author:

Fukuda K., Matsushita H., Sakabe H. and Takemoto K.

Year:

1981

Bibliographic source:

Gann, 72: 655-664

Materials and methods

Principles of method if other than guideline:

- Carcinogenicity in vivo after repeated dermal application
- Two experiments were performed with different exposure durations and concentrations. Experiment II used 3 week old weanling mice while experiment III used 7 week old mice

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

α-chlorotoluene

EC Number:

202-853-6

EC Name:

α-chlorotoluene

Cas Number:

100-44-7

Molecular formula:

C7H7Cl

IUPAC Name:

(chloromethyl)benzene

Constituent 2

Reference substance name:

chloromethylbenzene

IUPAC Name:

chloromethylbenzene

Details on test material:

- Name of test material (as cited in study report): benzyl chloride (BYC)
- Supplier: Wako Pure Chemical Industries Co. Ltd., Tokyo
- Reagent grade commercial material
No further information

Test animals

Species:

mouse

Strain:

ICR

Sex:

female

Administration / exposure

Route of administration:

dermal

Vehicle:

other: benzene

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Experiment II: 41 weeks
Experiment III: 50 weeks

Frequency of treatment:

Experiment II: 3/w 4 w, 2/w 37 w
Experiment III: 2/w 50 w

Post exposure period:

Experiment II: none
Experiment III: 32 weeks

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
10 μl/animal/painting (Experiment II)
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2.3 μl/animal/painting (Experiment III)
Basis:
nominal conc.

No. of animals per sex per dose:

Experiment II: 11 animals per dose (10 animals in control group)
Experiment III: 20 animals per dose

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Relevance of carcinogenic effects / potential:

In experiment II no deaths or tumors were observed. Mice exposed to benzyl chloride in experiment III on the other hand did develop tumors (5/20) and mortality was 50%. The tumors found in the treated animals were skin carcinomas, lung adenomas and leiomyosarcoma of the uterus. In the control mice from experiment III only 20% mortality was observed and 2 mice developed lung adenomas. Although a difference was noted between these two groups, this could not be statistically supported which is most likely a result of the limited group size. Benzyl chloride is however considered a weak carcinogen.

Effect levels

Dose descriptor:

NOAEL

Basis for effect level:

other: NOAEL could not be determined due to the study design

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Any other information on results incl. tables

Experiment II:

No skin papilloma was observed

Table showing mortality, total number of mice with number and number of mice with specific tumors.

	Dose per application (mg)	Total dose (mg)	Mortality (%)	Number of mice with tumor	Number of mice with specific tumor
					Skin carcinoma	Skin papilloma	Lung carcinoma	Lung adenoma	Thymus lymph
Control	0	0	0	0/10	0/10	0/10	0/10	0/10	0/10
10 μL	11.4	977	0	0/11	0/11	0/11	0/11	0/11	0/11

Experiment III:

First skin papilloma 374 days after the first application

Table showing mortality, total number of mice with number and number of mice with specific tumors.

	Dose per application (mg)	Total dose (mg)	Mortality (%)	Number of mice with tumor	Number of mice with specific tumor
					Skin carcinoma	Skin papilloma	Lung carcinoma	Lung adenoma	Others
Control	0	0	20	2/20	0/20	0/20	0/20	2/20	0
2.3 μL	2.55	255	50	5/20	3/20	0/20	0/20	2/20*	1**

* 1 multiple lung adenoma ** Leiomyosarcoma of the uterus Two of the skin carcinomas metastasized to the primary lymphatic organs, liver or kidneys. But these tumor incidences are not statistically significant.

Applicant's summary and conclusion

Conclusions:

The authors tested the carcinogenicity of benzyl chloride by painting the clipped back of ICR female mice in two different sets of sub-chronic experiments. The authors observed no deaths or tumors in experiment II. On the other hand, in experiment III, 5 out of 20 mice developed tumors such as squamous–cell carcinomas of the skin of which some metastasized to the primary lymphatic organs, liver or kidneys, others developed leiomyosarcoma of the uterus and lung adenomas. In the control group two of 20 animals developed lung adenomas. Although these results indicate a difference between the control and treated group, this observation could not be statistically supported probably as a result of the limited size of the groups. Hence benzyl chloride is considered a weak carcinogen.

Executive summary:

The authors tested the carcinogenicity of benzyl chloride (CAS n° 100-44-7) by painting the clipped back of ICR female mice in two different sets of sub-chronic experiments. In experiment II mice received 10 μL/animal/painting, three times a week during 4 weeks and then twice a week for 37 weeks. In experiment III mice received 2.3 μL/animal/painting twice a week during 50 weeks. The dose in experiment II corresponds to a total of 977 mg approximately (i.e. 11.4 mg/). For experiment III the total dose was approximately 255 mg (2.55 mg/application). At the end of the exposure period or when the test animals died or morbidity occurred, tumors were diagnosed and counted.

 

In experiment II neither mortality nor tumors were observed in the control and treated group. In experiment III mortality at the end of exposure was 20% in the control and 35% in the treated group. In the control group 2/20 mice had lung adenomas while in the treated group 5/20 had tumors. Of the latter group three mice had squamous–cell carcinomas of the skin of which two metastasized to the primary lymphatic organs, liver, or kidneys. Furthermore 1 of the treated mice had a leiomyosarcoma of the uterus and 2 others had lung adenomas. Finally the first skin papilloma was noted 374 days after the first application. Although a difference between the control and treated group was seen in experiment III, the difference in skin cancer incidence was not statistically significant between the two groups most likely because of the limited size of the experimental group. Anyhow in none of the controls performed in this entire study skin tumors were noted. Therefore the skin tumors in the treated mice are assumed to be caused by the test substance and as a result benzyl chloride is considered a weak carcinogen.

 

The GLP status of the study is unknown, but the study is sufficiently described although it would benefit from a larger number of test animals to enable a more precise statistical analysis.Nevertheless, these experiments are based on generally well accepted scientific principles. Thus this study should be considered reliable with restrictions, a Klimisch 2e study.