Benzoyl chloride

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

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:

Benzoyl chloride

EC Number:

202-710-8

EC Name:

Benzoyl chloride

Cas Number:

98-88-4

Molecular formula:

C7H5ClO

IUPAC Name:

benzoyl chloride

Test material form:

liquid

Test animals

Species:

mouse

Strain:

ICR

Sex:

female

Administration / exposure

Type of coverage:

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

Doses / concentrations 2

Remarks:

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

No. of animals per sex per dose:

Experiment II: 10 animals per group
Experiment III: 20 animals per group

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:

not specified

Dermal irritation:

not specified

Mortality:

not specified

Food consumption and compound intake (if feeding study):

not specified

Effect levels

1

Dose descriptor:

NOEL

Remarks on result:

other: Effect level not specified

2

Dose descriptor:

NOAEL

Remarks on result:

other: no NOAEL identified

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 as well as jumping, running and scratching of the painted area.

- 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. These lesions were rather severe.

 

Experiment II:

- Total dose: 538 and 1077 mg/animal respectively for application of 5 and 10 µL with each treatment

- No deaths occurred for all treatments

- Benzoyl chloride exhibited tumorigenic activity for the skin with low incidence (5µL/animal/painting)

- For animals painted with 5 µL/animal/ painting 2 out of the 10 mice (20%) developed skin tumors (i.e. one developed carcinomas of the skin and the other skin papilloma)

- In the test group with mice painted with 10 µL/animal/painting 3 out of 10 mice (30%) had lung adenomas. No other tumors were detected.

- In the control group no mortality nor tumors were noted.

 

Experiment III:

- Total dose: 284 mg/animal

- Mortality at termination of this experiment was 20% in the control and 5% in the treated group.

- In total 7 mice had tumors. Two animals from the test group developed squamous–cell carcinomas of the skin and 5 had lung adenoma

- In the control group 2 mice had lung adenomas

Applicant's summary and conclusion

Conclusions:

The authors tested the repeated dose toxicity of benzoyl chloride by painting the clipped back of ICR female mice using two different sub-chronic experiments. They observed a few minutes after application of the test substance marked irritation of the eyes, the skin and the respiratory tract as well as jumping, running and scratching of the painted area. 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 was noted for all treated groups. While in the control group no tumors were observed, 2 mice from the lowest dose group (5µL/animal/painting) had skin tumors (i.e. 1 carcinoma and 1 papilloma skin tumor). For the test group with the highest dose (10µL/animal/painting) three mice had lung adenomas.
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 benzoyl chloride (CAS n° 98-88-4) by painting the clipped back of ICR female mice using two different sub-chronic experiments. In experiment II two doses (5 and 10 μl/animal/painting) were applied 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 538 and 1077 mg applied during the entire exposure period for treatment with 5 and 10 µL/animal/painting respectively. The dose applied in experiment III was approximately 284 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 jumping, running and scratching of the painted area were observed. 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 for all treatments but benzoyl chloride exhibited tumorigenic activity for the skin with low incidence. Indeed, when exposed to the lowest dose (5 µL/animal/ painting) 2 out of the 10 mice (20%) developed skin tumors (i.e. one developed carcinomas of the skin and the other skin papilloma). In the test group painted with the highest dose (10 µL/animal/painting) however, 3 out of 10 mice (30%) had lung adenomas and no other tumors were detected. In the experiment III mortality at termination was 20% for the control and 5% in the treated group. The number of mice with tumors in the treated group was 7/20 (35%). Two mice developed squamous–cell carcinomas of the skin and 5 others had lung adenomas. Also in the control group 2 mice had lung adenomas but no other tumors.

 

None of the effects reported allowed a derivation of the NOEL or NOAEL. The results do suggest however a weak carcinogenic potential of benzoyl chloride. The GLP status of the study is unknown. Although the study is sufficiently described further investigation on the clinical signs would be preferable. Nevertheless, these experiments are based on generally well accepted scientific principles. Therefore, this study should be considered reliable with restrictions, a Klimisch 2e study.