Chloroacetonitrile

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1985

Materials and methods

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Chloroacetonitrile

EC Number:

203-467-0

EC Name:

Chloroacetonitrile

Cas Number:

107-14-2

Molecular formula:

C2H2ClN

IUPAC Name:

2-chloroacetonitrile

Test material form:

liquid

Specific details on test material used for the study:

greater than 99% pure

Test animals

Species:

mouse

Strain:

Sencar

Sex:

female

Details on test animals or test system and environmental conditions:

Female Sencar mice were obtained from Dr. T. Slaga of Oak Ridge National Laboratories, Oak Ridge, Tennessee

Administration / exposure

Route of administration:

dermal

Vehicle:

acetone

Details on exposure:

Chloroacetonitrile was applied in acetone to the shaved back. Six doses were applied over a 2-week period for total doses of 1200, 2400, and 4800 mg/kg (or 24, 48, and 96 mg/mouse).

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

6 doses

Post exposure period:

Animals from the initiation/promotion experiments were maintained for one year to determine the incidence of squamous cell carcinomas resulting from the exposure to haloacetonitrile compounds.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

200 other: mg/kg

Remarks:

equivalent to 4 mg/mouse, total dose of 1200 mg/kg or 24 mg/mouse (6 doses)

Doses / concentrations 2

Dose / conc.:

400 other: mg/kg

Remarks:

equivalent to 8 mg/mouse, total dose of 2400 mg/kg or 48 mg/mouse (6 doses)

Doses / concentrations 3

Dose / conc.:

800 other: mg/kg

Remarks:

equivalent to 16 mg/mouse, total dose of 4800 mg/kg or 96 mg/mouse (6 doses)

No. of animals per sex per dose:

40 animals in each exposure group

Control animals:

yes, concurrent vehicle

Details on study design:

Two weeks after the last dose of the haloacetonitriles a promotion schedule involving the application of 1.0 μg of TPA in 0.2 ml acetone 3 times weekly was begun and continued for 20 weeks.
Complete carcinogenic activity of the haloacetonitriles was assessed in a separate experiment where 800 mg/kg of chloroacetonitrile was applied three times weekly for 24 weeks and animals observed for papilloma development.
Experiments were also conducted utilizing the oral route of exposure. In this case, doses were limited to a maximum dose of 50 mg/kg administered six times over a 2-week period to avoid the acute toxic effects of these chemicals. Further conduct of these experiments was identical to the initiation/promotion experiments.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

The appearance and regression of tumors were charted weekly. Papillomas were included in the tumor count only if they were observed for three consecutive weeks at the same location.

Sacrifice and pathology:

At necropsy all gross lesions were recorded and tissues with lesions were fixed in 10% buffered formalin for subsequent histopathological evaluation. The data for each dose group were analyzed for a significant increase over the respective control response using Fisher's Exact Test.

Statistics:

The count of the total tumors and data on time to first tumor occurrence were analyzed for dose-response with a trend test based on Cox's regression model (Cox, 1972; Tarone, 1975).

Results and discussion

Results of examinations

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Although there was a tendency in individual experiments involving oral exposures for increased papilloma yields with treatments by individual haloacetonitriles, there were no statistically significant differences in the total number of tumors or in the time to first tumor when all experiments were combined for statistical analysis. The response to an oral dose of urethane (300 mg/kg), as a positive control, did produce an increase in papilloma yield consistent with past experience in our laboratory with the Sencar mouse.
The haloacetonitriles were active as tumor initiators when applied topically to the shaved back of the Sencar mouse. All of the haloacetonitriles produced increases in the average cumulative number of tumors per animal. Clearly dose-related increases in cumulative papilloma count were observed with chloroacetonitrile (p = 0.02). In the case of chloroacetonitrile the incidence of squamous cell carcinomas was increased significantly (p < 0.05) over that observed in the control groups. The only exception to this was that the high dose of chloroacetonitrile produced a larger proportion of squamous cell carcinomas than would have been predicted from the papilloma yield.

Relevance of carcinogenic effects / potential:

Chloroacetonitrile initiated tumors in the mouse skin with topical applications followed by a 20-week promotion schedule of 12-O-tetradecanoylphorbol-13-acetate (TPA) applications (p < 0.02).