Toxicology and carcinogenesis studies of Telone II® (a soil fumigant containing approximately 89% cis- and trans-1,3-dichloropropene, 2.5% 1,2-dichloropropane, 1.5% of a trichloropropene isomer, and 1.0% epichlorohydrin) were conducted by administering the commercial-grade formulation in corn oil by gavage to groups of 52 male and 52 female F344/N rats at doses of 0, 25, or 50 mg/kg and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 50, or 100 mg/kg. Doses were administered three times per week for 104 weeks. Ancillary studies were conducted in which dose groups containing five male and five female rats were killed after receiving Telone II® for 9, 16, 21, 24, or 27 months.
Mean body weights of high dose male rats were about 5% lower than those for the vehicle control and low dose male rats; no differences in body weights were observed among groups of female rats. Survival was comparable for the different groups of male and female rats. For male and female mice, the dosed groups initially weighed 6%-22% less than did the vehicle controls; the weight differential decreased to 5%-9% by the end of the studies. Twenty-five vehicle control male mice died during weeks 48-51 from suppurative inflammation of the heart (myocarditis). At the end of the studies, the survival of male mice was as follows: vehicle control, 8/50; low dose, 28/50; high dose 31/50. Survival of female mice was lower (P<0.05) in the high dose group than in the vehicle controls (46/50; 45/50; 36/50).
The primary organs affected were the forestomach (rats and mice), urinary bladder (mice), lung (mice), and liver (rats). Compound-related nonneoplastic lesions included basal cell or epithelial hyperplasia of the forestomach (rats and mice), epithelial hyperplasia of the urinary bladder (mice), and kidney hydronephrosis (mice). Neoplastic lesions associated with administration of Telone II® included squamous cell papillomas of the forestomach (male rats: 1/52; 1/52; 9/52; female rats: 0/52; 2/52; 3/52; female mice: 0/50; 1/50; 2/50), squamous cell carcinomas of the forestomach (male rats: 0/52; 0/52; 4/52; female mice: 0/50; 0/50; 2/50), transitional cell carcinomas of the urinary bladder (female mice: 0/50; 8/50; 21/48), alveolar/bronchiolar adenomas (female mice: 0/50; 3/50; 8/50), and neoplastic nodules of the liver (male rats: 1/52; 6/52; 7/52).
Although the study in male mice was considered inadequate due to the deaths at weeks 48-51 of 25/50 vehicle control animals, 2/50 of the high dose males had transitional cell carcinomas of the urinary bladder. Furthermore, increases were seen in the incidences of alveolar/bronchiolar neoplasms of the lung (1/50; 13/50; 12/50) and of squamous cell papillomas of the forestomach (0/50; 2/50; 3/50). These findings plus the finding of nonneoplastic lesions in two of these organs (basal cell or epithelial hyperplasia of the forestomach: 0/50; 0/50; 4/50; epithelial hyperplasia of the urinary bladder: 0/50; 9/50; 18/50) suggest that Telone II® may have been responsible for the development of these lesions in male mice.
Development of lesions of the forestomach (basal cell hyperplasia and squamous cell papilloma) was observed to be time dependent. The results of the scheduled kills supported the findings of the carcinogenesis studies. When the results from the scheduled kills at all time points were pooled with those of the 24-month carcinogenesis studies, the incidences were as follows: basal cell or epithelial hyperplasia of the forestomach-- male rats: 3/77; 13/77; 31/77; female rats: 1/75; 5/77; 35/77; squamous cell papilloma of the forestomach-- male rats: 1/77; 1/77; 13/77; female rats: 0/75; 2/77; 8/77; neoplastic nodules of the liver--male rats: 1/77; 6/76; 8/77; female rats: 6/75; 8/77; 12/77.
cis- and trans-1,3- Dichloropropane are the principle components (89%) in Telone II®, but the 1.0% epichlorohydrin, a direct-acting mutagen and carcinogen added as a stabilizer, may have influenced the development of the forestomach lesions.
1,3-Dichloropropene was mutagenic in Salmonella typhimurium strains TA98, TA100, and TA1535 without metabolic activation and in TA100 and TA1535 with metabolic activation by Aroclor-induced male Sprague-Dawley rat and Syrian hamster liver S9. No mutagenic response was seen in TA1537. Sex-linked recessive lethal mutations were observed in Drosophila melanogaster, and 1,3-dichloropropene did not induce reciprocal translocations in D. melanogaster.
A data audit was conducted on the Telone II® 2-year carcinogenesis studies in rats and mice and the ancillary studies in rats. Except for the already known problem of survival of male vehicle control mice, no other discrepancies or problems that would compromise the validity of the findings or alter the interpretations of these studies were found.
Under the conditions of these gavage studies, there was clear evidence of carcinogenicity for male F344/N rats, as indicated by Telone II®-related increased incidences of squamous cell papillomas and carcinomas of the forestomach, as well as an increased incidence of neoplastic nodules of the liver. In female F344/N rats, there was some evidence of carcinogenicity because Telone II® caused an increased incidence of squamous cell papillomas of the forestomach. The experiment in male B6C3F1 mice was considered to be an inadequate study of carcinogenicity because of reduced survival in the vehicle control group. However, there was some indication in the male mice of Telone II®-related increases of transitional cell carcinomas of the urinary bladder, squamous cell papillomas of the forestomach, and alveolar/bronchiolar adenomas and carcinomas of the lung. There was clear evidence of carcinogenicity for female B6C3F1 mice, since Telone II® caused increased incidences of transitional cell carcinomas of the urinary bladder; Telone II® also increased the incidences of alveolar/bronchiolar adenomas of the lung and of squamous cell papillomas or carcinomas of the forestomach in the female mice. Telone II®-related nonneoplastic lesions included basal cell or epithelial cell hyperplasia in the forestomach of male and female rats and male and female mice and epithelial hyperplasia of the urinary bladder in male and female mice.