title: NTP Toxicology and Carcinogenesis Studies of 1-Chloro-2-propanol (Technical Grade) (CAS NO. 127-00-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies.
abstract: 1-Chloro-2-propanol and its positional isomer, 2-chloro-1-propanol, are used as chemical intermediates for the manufacture of propylene oxide, a starting material for production of polyurethane polyols and propylene glycol. The National Cancer Institute nominated 1-chloro-2-propanol for study because of potential for human exposure due to its residues in various foods that are fumigated with ethylene oxide or propylene oxide. Male and female F344/N rats and B6C3F1 mice were exposed to technical grade 1-chloro-2-propanol (75% to 76%% 1-chloro-2-propanol; 24% to 25%% 2-chloro-1-propanol) in drinking water for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood erythrocytes. Continuous breeding studies were conducted in Sprague-Dawley rats. 14-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. Two 10,000 ppm females died before the end of the study. The final mean body weights and body weight gains of 3,300 and 10,000 ppm rats were significantly less than those of the controls; rats in the 10,000 ppm groups lost weight. Water consumption by the 3,300 and 10,000 ppm groups was significantly less than that by the controls throughout the study. The thymus weights of 10,000 ppm rats were significantly less than those of the controls. Exposure to 1-chloro-2-propanol caused cytoplasmic alteration and degeneration of the acinar cells and fatty change in the pancreas, atrophy of the bone marrow, and atrophy and hematopoiesis of the spleen in males and females. 14-DAY STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. One male mouse in the 10,000 ppm group died before the end of the study. Mean body weight gains of 10,000 ppm mice were significantly less than those of the controls. Water consumption by 3,300 and 10,000 ppm males and females was significantly less than that by the controls throughout the study. Liver weights of 1,000, 3,300, or 10,000 ppm males and females were significantly greater and thymus weights of 10,000 ppm mice were significantly less than those of the controls. Exposure to 1-chloro-2-propanol caused hepatocellular vacuolization, cytoplasmic alteration and degeneration of the pancreas acinar cells, and atrophy of the spleen in males and females. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 1-chloro-2-propanol at concentrations of 0, 33, 100, 330, 1,000, or 3,300 ppm (equivalent to average daily doses of approximately 5, 10, 35, 100, or 220 mg/kg) for 14 weeks. All rats survived to the end of the study. Mean body weight gains of 3,300 ppm rats were significantly less than those of the controls. Water consumption by the 3,300 ppm male and female rats was significantly less than that by the controls. A minimal to mild anemia was observed in exposed female rats. The cauda epididymis and epididymis weights of 3,300 ppm males were significantly less than those of the controls. The percentage of abnormal sperm in 3,300 ppm males and the concentration of epididymal sperm in 330 ppm males were significantly increased compared to the controls. Kidney and liver weights of males and females exposed to 100 ppm or more were generally greater than those of the controls. The incidences of acinar cell degeneration and fatty change of the pancreas in 1,000 and 3,300 ppm rats, hepatocytic metaplasia of the pancreatic islets in 3,300 ppm females, cytoplasmic vacuolization of the liver in 100, 1,000 and 3,300 ppm males, and renal tubule epithelium regeneration in 3,300 ppm females were increased compared to the controls. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 33, 100, 33entrations of 0, 33, 100, 330, 1,000, or 3,300 ppm (equivalent to average daily doses of approximately 5, 15, 50, 170, or 340 mg/kg to males and 7, 20, 70, 260, or 420 mg/kg to females) for 14 weeks. One 330 ppm male died before the end of the study. Mean body weight gains of exposed groups were similar to those of the controls. A minimal anemia was observed in 3,300 ppm males. The right epididymis weight of 3,300 ppm males was significantly greater than that of the controls. Kidney weights of 3,300 ppm mice, liver weights of 1,000 ppm males and of all exposed groups of females, and thymus weights of 1,000 and 3,300 ppm females were greater than those of the controls. The incidences of pancreatic acinar cell degeneration and fatty change in 3,300 ppm males and females and cytoplasmic vacuolization of the liver in all groups of exposed females were significantly increased compared to the controls. The severities of renal tubule cytoplasmic vacuolization were greater in 1,000 and 3,300 ppm males than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were administered drinking water containing 0, 150, 325, or 650 ppm 1-chloro-2-propanol (equivalent to average daily doses of approximately 15, 30, or 65 mg/kg during the first several months of the study and 8, 17, or 34 mg/kg for the remainder of the 2-year study) for up to 105 weeks. Survival of all exposed groups was similar to that of the controls. Mean body weights of exposed rats were generally similar to those of the controls throughout most of the study. Water consumption by all exposed groups was similar to that by the controls. No treatment-related neoplasms or nonneoplastic lesions were observed in this study. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were administered drinking water containing 0, 250, 500, or 1,000 ppm 1-chloro-2-propanol (equivalent to average daily doses of approximately 45, 75, or 150 mg/kg to males and 60, 105, or 210 mg/kg to females during the first several months of the study and 25, 50, or 100 mg/kg for the remainder of the 2-year study) for up to 105 weeks. Survival of all exposed groups was similar to that of the controls. The mean body weights of all exposed mice were generally similar to those of the controls throughout the study. Water consumption by all exposed groups was similar to that by the controls. No treatment- related neoplasms or nonneoplastic lesions were observed in this study. GENETIC TOXICOLOGY: 1-Chloro-2-propanol is a demonstrated mutagen in vitro. It was weakly mutagenic in S. typhimurium strain TA100 in the presence of hamster or rat liver S9 activation enzymes and was positive, with and without S9, in TA1535. No mutagenic activity was detected in strains TA97, TA98, and TA1537, with or without S9. In cytogenetic tests with Chinese hamster ovary cells, 1-chloro-2-propanol induced high levels of sister chromatid exchanges and chromosomal aberrations in the presence and the absence of S9. The marked ability of 1-chloro-2-propanol to induce chromosomal effects in vitro was not seen in vivo. Positive results were obtained in a test in D. melanogaster for induction of sex-linked recessive lethal mutations in germ cells of males administered 1-chloro-2-propanol via injection; however, negative results were obtained when males were administered 1-chloro-2-propanol in feed. A subsequent germ cell reciprocal translocation test in D. melanogaster yielded negative results. Further, no induction of micronucleated erythrocytes was observed in peripheral blood of male and female mice administered 1-chloro-2-propanol via drinking water for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female F344/N rats exposed to 150, 325, or 650 ppm. There was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female B6C3F1 mice exposed to 250, 500, or 1,000 ppm. Synonyms: 1-Chloro-2-hydroxypropane, 1-chloroisopropyl alcohol, propylene-&alpha;-chlorohydrin, sec-propylene chlorohydrin