title: NTP Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone (CAS No. 532-27-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
abstract: 2-Chloroacetophenone is a potent lacrimator that has been used as a riot control agent and in tear gas formulations for personal protection devices. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to air containing 2-chloroacetophenone vapor for 14 days, 13 weeks, 15 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: In 14-day studies, exposure concentrations of 2-chloroacetophenone ranged from 4.8 to 64 mg/m3. All rats exposed to 19, 43, or 64 mg/m3 died during the first week of the studies and 1/5 male rats exposed to 10 mg/m3 died during the second week of the study. Rats exposed to 10 mg/m3 lost weight; the final mean body weights of male or female rats exposed to 4.8 mg/m3, the lowest concentration used, were 23% or 15% lower than that of controls. During the exposure, rats showed partial closure of the eyelids, excessive lacrimation (dacryorrhea), dyspnea, and erythema. All mice exposed to 10 mg/m3 or higher concentrations of 2-chloroacetophenone died during the first week of the studies. The final mean body weights of mice exposed to 4.8 mg/m3 were similar to those of controls. Dacryorrhea was observed in exposed mice. Thirteen-Week Studies: The exposure concentrations of 2-chloroacetophenone ranged from 0.25 to 4 mg/m3 for rats and mice. All rats lived to the end of the studies. The final mean body weights of rats exposed to 4 mg/m3 were 9% lower than those of controls. Eye irritation during exposure was evident in rats exposed to 0.5 mg/m3 or higher concentrations of 2-chloroacetophenone. One of 10 female mice exposed to 4 mg/m3 and 1/10 female mice exposed to 0.5 mg/m3 died before the end of the study. The final mean body weights of exposed mice were 7%-12% lower than that of controls for males and 12%-15% lower for females. No chemical-related gross or microscopic lesions were observed in rats or mice. In the 2-year studies, groups of 60 rats of each sex were exposed to a vapor of 0 (chamber control), 1, or 2 mg/m3 (0, 0.15, or 0.3 ppm) 2-chloroacetophenone, 6 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed to 0 (chamber control), 2, or 4 mg/m3 (0, 0.3, or 0.6 ppm) on the same schedule. Ten animals from each group were killed and examined at 15 months; the remaining animals continued on study for 2 years. Fifteen-Month Studies: In the 15-month studies, minimal-to-mild focal squamous metaplasia and hyperplasia of the respiratory epithelium were seen at increased incidences in rats exposed to 2 mg/m3. No exposure-related lesions were observed in mice of either sex. Body Weight and Survival in the Two-Year Studies: Mean body weights and survival of exposed and chamber control rats were similar throughout most of the studies (survival-male: control, 14/50; 1 mg/m3, 22/50; 2 mg/m3, 17/50; female: 23/50; 20/50; 24/50). Mean body weights of male mice exposed to 4 mg/m3 were about 5%-12% lower than those of controls after week 30; small differences between mean body weights of exposed and control female mice were not clearly exposure related. The survival of female mice exposed to 2 mg/m3 was significantly lower than that of chamber controls after week 98. No other differences in survival were observed between any groups of mice (male: control, 34/50; 2 mg/m3, 36/50; 4 mg/m3, 33/50; female: 40/50; 28/50; 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Fibroadenomas of the mammary gland occurred in female rats with positive trends, and the incidence in the 2 mg/m3 group was greater than that in chamber controls (control, 12/50; 1 mg/m3, 19/50; 2 mg/m3, 23/50). The incidences of adenomas or adenocarcinomas of the mammary gland were not increased in the exposed groups. Minimal-to-mild suppurative inflammation of the nasal mucosa was observed at increased incidences in exposed male rats. Hyperplasia and squamous metaplasia of the nasal respiratory epithelium were observed at increased incidences in exposed ry epithelium were observed at increased incidences in exposed male and female rats. In mice, squamous metaplasia of the respiratory epithelium of the nasal passage was seen in four females and two males exposed to 4 mg/m3 2-chloroacetophenone. Inflammation, ulcers, and squamous hyperplasia of the forestomach were observed at increased incidences in exposed female rats. Genetic Toxicology: 2-Chloroacetophenone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In cytogenetic tests with CHO cells, 2-chloroacetophenone did not induce sister chromatid exchanges with or without activation, but a weak positive increase in chromosomal aberrations was observed in the absence of metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of 2-chloroacetophenone for male rats exposed to 1 or 2 mg/m3. There was equivocal evidence of carcinogenic activity for female F344/N rats, based on a marginal increase in fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 2 or 4 mg/m3 2-chloroacetophenone. Synonyms: a-chloroacetophenone; 2-chloro-1-phenylethanone; CN; phenacyl chloride; phenylchloromethylketone Trade Names: Mace&reg;.; Chemical Mace&reg;.