Subchronic toxicity study of 1,4-dithiane in the rat

Abstract

In a 90-day study, CD strain rats were dosed with 1,4-dithiane by daily gavage at 0, 105, 210, and 420 mg/kg/day (30 rats/sex/dose) in order to calculate a suggested drinking water criterion. No overt toxicity, treatment-related mortality, or ophthalmologic changes were found. Treatment-related decreases were found in female amylase, sorbitol dehydrogenase, and reticulocyte count, and in LDH 1 in both sexes, in LDH 3 in the males, and in LDH 5 in both sexes. Treatment-related increases were found in female liver and in male kidney and male thymus weight. A treatment-related decrease in female brain weight was also found. Significant changes in organ weight of dosed animals compared to control organ weight were observed at the 105 mg/kg/day dose in the spleen of both sexes, female brain, and the male kidneys. Three organs showed compound-related anatomic changes: nose, liver, and kidney. Anisotrophic crystals of undertermined chemical composition were deposited in the olfactory nasal mucosa of both sexes. These crystals were not composed of 1,4-dithiane because 1,4-dithiane is very soluble in ethanol and would not have been present after the slide preparation process. The crystals were present in similar amounts in both sexes of the high and intermediate dose groups. In the low dose group, however, the crystals were present in greater amounts in the females. Crystals were not observed in the control animals. The other treatment-related anatomic abnormalities were eosinophilic cytoplasmic granulation of the convoluted renal tubule cells in the high dose males and minimal hypertrophy of the centrilobular region of the liver in the high dose females. The animal no-observed-effect-level was 105 mg/kg/day. This study reports a novel form of toxicity (deposition of anisotrophic crystals in the olfactory mucosa) from 1,4-dithiane administered by gavage. The chemical composition of the crystals and the absorption, distribution, metabolism, and excretion of 1,4-dithiane are unknown at present.