α-chlorotoluene

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study fulfils generally well accepted scientific criteria and is sufficiently described. Klimisch 2e

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:

- The backs of the ICR mice were clipped free of hair before treatment and clipping was repeated when necessary.
- Benzene solutions of the test material were prepared just prior to treatment. The dorsal skin application was done with a micropipette.
- Three experiments were performed with different exposure durations and concentrations. Experiment II used 3 week old weanling mice and experiment III 7 week old mice
- When moribund or at the indicated time mice were ether killed and completely necropsied. After gross pathological inspection the organs and
tumors were exised , fixed, paraffin embedded, 5 μm sections made and stained appropiately for histological evaluation.

GLP compliance:

not specified

Limit test:

no

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)
- Reagent grade commercial material
- Supplier: Wako Pure Chemical Industries Co. Ltd., Tokyo
No further information

Test animals

Species:

mouse

Strain:

ICR

Sex:

female

Administration / exposure

Type of coverage:

other: No, painted

Vehicle:

other: benzene

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Experiment II: 41 weeks
Experiment III: 50 weeks (terminated after 18.7 months.)

Frequency of treatment:

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

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
10 μl/animal/painting (Experiment II)
Basis:
nominal per unit area

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2.3 μl/animal/painting (Experiment III)
Basis:
nominal per unit area

No. of animals per sex per dose:

Experiment II: 10 animals in control group, 11 animals (dose level 10 μl/animal/painting)
Experiment III: 20 animals per dose

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Basis for effect level:

other: None of the effects reported allowed to derive a NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

2

Dose descriptor:

NOEL

Basis for effect level:

other: None of the effects reported allowed to derive a NOEL

Remarks on result:

not measured/tested

Remarks:

Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

- During a few minutes after dermal painting of mice a marked irritation of the eyes, the skin and the respiratory system and a decrease in motor activities was observed.

- At the painted area first erythema and swelling were noted later alopecia, induration, marked keratinization and in some mice ulcers and/or necrosis of the epidermis were observed.

Experiment II:

- Total dose: 979 mg/animal

- No deaths occurred

- No tumor was found in benzene–treated controls or test animals

Experiment III:

- Total dose: 258 mg/animal

- Mortality at termination was 20% in the controls compared and 50% in the treated group.

- 3 mice of the test group developed squamous–cell carcinomas of the skin (of which 2 in metastasis), 1 had a leiomyosarcoma of the uterus; 2 treated and 2 control mice had lung adenomas. The difference in skin cancer incidence was not statistically significant between the two group

Applicant's summary and conclusion

Conclusions:

The authors tested the repeated dose toxicity of benzyl chloride by painting the clipped back of ICR female mice using two different sub-chronic experiments. The authors observed a few minutes after application of the test substance marked irritation of the eyes, the skin and the respiratory tract as well as a decrease in motor activities. At the painted area first erythema and swelling were noted, later-on alopecia, induration, marked keratinization, and in some mice ulceration and/or epidermal necrosis. In experiment II no mortality nor tumors were noted, while in experiment III mortality at termination was 50% in the treated group and tumors were observed at treated skin. Neither a NOEL nor a NOAEL could be derived since the experiment was not adequately designed.

Executive summary:

The authors tested the repeated dose toxicity of benzyl chloride (CAS n° 100-44-7) by painting the clipped back of ICR female mice using two different 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 the second experiment (III), mice received 2.3 μl/animal/painting twice a week during 50 weeks. The dose in experiment II corresponded to approximately 979 mg applied during the entire exposure period and the dose applied in experiment III was approximately 258 mg. Immediate reactions, mortality and pathological signs were monitored and tumors were diagnosed and counted in all animals at their death or at the end of the exposure period.

Generally, a few minutes after dermal painting of the treated mice a marked irritation of the eyes, the skin and the respiratory system as well as decreased motor activities were seen. Furthermore, at the painted area first erythema and swelling were noted later alopecia, induration, marked keratinization and in some mice ulcers and/or necrosis of the epidermis. More specifically, in experiment II no mortality was observed, and the treated as well as the control mice were free of tumors. In the experiment III mortality at termination was 20% for the control and 50% in the treated group. The number of mice with tumors in the treated group was 5/20 (25%). Threemice of the test group developed squamous–cell carcinomas of the skin (of which 2 in metastasis), 1 had a leiomyosarcoma of the uterus and 2 treated had lung adenomas. Within the control group 2 mice had lung adenomas as well.

 

None of the effects reported allowed a derivation of the NOEL or NOAEL. They only show evidence of the weak carcinogenic potential of benzyl chloride. The GLP status of the study is unknown, but it is sufficiently described although further investigation on the clinical signs would be preferable. Moreover, due to the small size of the group, only statistical analysis was performed for experiment III. Nevertheless, these experiments are based on generally well accepted scientific principles. Therefore, this study should be considered reliable with restrictions, a Klimisch 2e study.