Carcinogenesis Studies of Pentachloroethane (CAS No. 76-01-7) in F344/N Rats and B6C3F1 Mice (Gavage Study)
Chemical Formula: C2HCl5
A carcinogenesis bioassay of technical grade pentachloroethane (95.5% pure, with 4.2% hexachloroethane) was conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/ N rats at doses of 75 or 150 mg/ kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 250 or 500 mg/ kg. (Pentachloroethane is a solvent that was used primarily as an intermediate in the manufacture of tetrachloroethylene.) Doses were administered for 103 weeks for rats and 41-103 weeks for mice. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Prechronic testing (single-dose and 14-day and 13-week repeated-dose studies) did not indicate target organ toxicity for pentachloroethane. The dosage levels for the 2-year study were selected on the basis of survival and body weight gains during the prechronic test phase.
Survival of high-dose rats of each sex was significantly (P<0.05) less than that of the controls. Mean body weights of dosed male and female rats were lower than those of the corresponding controls during the second year of the study. Final mean body weights for rats were 4%-5% lower for male rats and 8%-12% lower for female rats when compared to controls.
Chronic, diffuse inflammation of the kidney, distinguishable from nephropathy seen in aging F344/ N rats, was found in male rats in a significant (P<0.001) and dose-related incidence (control, 4/50, 8%; low-dose, 14/49, 29%; high-dose, 33/50, 66%). Mineralization of the renal papilla, considered to be secondary to chronic inflammation, was also observed at increased incidences in dosed male rats.
Pentachloroethane administration did not cause any increased incidences of tumors in either male or female rats. [See Note Added Subsequent to Peer Review.] Statistically significant negative trends were detected for subcutaneous tissue fibromas among males and for pituitary adenomas in both sexes.
Forty-two high-dose male mice died by week 41, and the 8 remaining animals in the group were killed at that time. Twenty-five male control mice were killed at week 44 to serve as controls for the high-dose males. Only 22/50 (44%) of the low-dose male mice survived to the end of the study. All high-dose female mice were dead by week 74, and only 9/50 (18%) low-dose females survived to the end of the study. Mean body weights of mice were lower than those of controls.
The incidence of hepatocellular carcinoma was significantly elevated in all groups of dosed mice (male: 4/48, 8%; 26/44, 59%, P<0.001; 7/45,16%; female: 1/46, 2%; 28/42, 67%, P<0.001; 13/45, 29% P<0.001). Early mortalities in the high-dose male mice precluded an evaluation of their lifetime incidence of hepatocellular carcinoma. There was a significant increase in incidence over that observed among 25 controls killed at week 44 (0/25 versus 7/45, P<0.05). There was also a significant (P<0.001) dose-related increase in hepatocellular adenoma in female mice (2/46, 4%; 8/42, 19%; 19/45, 42%).
Under the conditions of this bioassay, technical grade pentachloroethane containing 4.2% hexachloroethane (a known carcinogen in mice) was not carcinogenic in F344/N rats. The decreased survival of dosed rats might have reduced the sensitivity for a carcinogenic response in this species. Pentachloroethane was nephrotoxic to male rats. Technical grade pentachloroethane was carcinogenic for B6C3F1 mice, causing hepatocellular carcinomas in males and females, and adenomas in females.
NOTE ADDED SUBSEQUENT TO PEER REVIEW
After the Peer Review Panel meeting in June 1981, the National Toxicology Program determined that the kidney (especially in male F344/N rats) was a target organ for the short-chain chlorinated aliphatic hydrocarbons. This awareness came from the nonneoplastic and neoplastic diagnoses made on related chemicals in this class. Alerted to this lead, the NTP re-examined the originally-prepared histology slides on the rat kidney from the pentachloroethane bioassay. During the re-reading, additional renal tubular adenomas were discovered. Unfortunately, these slides were lost after they arrived at the Gulf South Research Institute laboratory; by necessity, a new set of slides was prepared.
In the second set of slides, three additional renal tubular-cell adenomas were discovered: one in a low-dose male and two in high-dose males; none were found in treated females or in male and female vehicle controls. Thus, rare tubular-cell adenomas of the kidney occurred in male rats with a dose-related trend (P<0.05), and the incidence in the high-dose group was suggestive (P<0.06; 0/50, 1/49, 4/50). Additionally, one control and one low-dose male each had an adenocarcinoma and another low-dose male had a carcinoma of the kidney (not otherwise specified); combining tubular-cell tumors reduced the statistical differences (1/50, 2/49, 4/50). These tumors are uncommon in male vehicle controls in the bioassay program, occurring in 1/293 (0.3%) at this bioassay testing laboratory and in 4/998 (0.4%) in all NCI/ NTP bioassay testing laboratories. All tumors in these gavage controls were adenocarcinomas. The National Toxicology Program considers that these rare tubular-cell tumors of the kidney in male rats indicate a target organ and may have been associated with the administration of pentachloroethane. These additional tumor diagnoses were not presented to the Peer Review Panel. These are, however, the incidence rates recorded and analyzed statistically in this technical report (See Table 5, Table Al, and Table A3 in the full document).
Report Date: April 1983