title: NTP Toxicity Studies of Sodium Cyanide (CAS No. 143-33-9) Administered by Dosed Water to F344/N Rats and B6C3F1 Mice.
abstract: Cyanide and its salts are used extensively in industry and manufacturing and are found in water and food consumed by humans. Chronic exposure to low levels of cyanide is suspected to be responsible for various neuropathic and thyrotoxic conditions in humans. Data in the literature indicate that long-term exposure to near-lethal concentrations of cyanide may produce lesions in rodents similar to those linked to chronic cyanide exposure in humans. However, few data are available on the effects of subchronic exposure to cyanide concentrations that are not acutely toxic. To address this lack of data, 13-week toxicity studies on cyanide were conducted with male and female F344/N rats and B6C3F1 mice administered low doses of sodium cyanide in drinking water. Animals were evaluated for histopathology, clinical chemistry, hematology, urine chemistry, and reproductive toxicity. In addition, the mutagenicity of sodium cyanide was assessed in Salmonella typhimurium. Groups of 10 rats and 10 mice per sex were administered sodium cyanide in drinking water at concentrations of 0, 3, 10, 30, 100, and 300 ppm for 13 weeks. No deaths attributed to sodium cyanide administration occurred in either species. In animals exposed to 300 ppm, male rats had slightly lower final mean body weights and mean body weight gains and female mice had slightly lower final mean body weights than the respective controls. Water consumption by rats and mice in the 100 and 300 ppm groups was 10% to 30% lower than that by the controls; however, no clinical signs attributable to sodium cyanide administration or to dehydration were observed. No gross or microscopic changes specifically related to cyanide toxicity occurred at any site in males or females of either species. In particular, no lesions were found in the brain or thyroid gland. Differences between absolute and relative organ weights of exposed and control animals were minor and sporadic and were not exposure concentration dependent; these differences were not considered to be related to sodium cyanide administration. Hematologic, clinical chemistry, and urinalysis evaluations of rats and mice revealed minimal changes that were not considered biologically significant, although the decreased urine volume and increased urine specific gravity observed in male rats in the 300 ppm group of the supplemental clinical pathology study were consistent with the observed decreases in water consumption. The concentration of urinary thiocyanate (the primary metabolite of cyanide) increased with increasing exposure concentration at all time points. Sperm motility and vaginal cytology examinations were performed on rats and mice in the 0, 30, 100, and 300 ppm groups. Sodium cyanide caused a slight reduction in cauda epididymal weight in all groups of exposed male rats and in male mice exposed to 300 ppm. In male rats, the number of spermatid heads per testis in the 300 ppm group was less than the number in the controls, and sperm motility in all exposed groups was marginally lower than in the controls. Sodium cyanide produced no adverse effects on estrous cyclicity in female mice, but at higher concentrations (100 and 300 ppm), sodium cyanide caused a significant increase in the amount of time spent by female rats in proestrus and diestrus relative to estrus and metestrus. Sodium cyanide was not mutagenic in Salmonella typhimurium strain TA100, TA1535, TA97, or TA98 with or without exogenous metabolic activation. In summary, administration of low concentrations of sodium cyanide in drinking water to rats and mice for 13 weeks resulted in no clinically significant body weight, organ weight, histopathologic, or clinical pathology changes. The absorption of administered cyanide was confirmed by increases in urinary thiocyanate excretion. Concentrations of 100 ppm and greater resulted in reduced water consumption. Thus, higher concentrations of sodium cyanide could not be administered by the drinking water route of administration. Alterations in reproductive parameters indicate that subchronic exposure to low concentrations of sodium cyanide may produce mild but significant adverse effects on rat reproductive systems. These changes are probably insufficient to decrease fertility in rats; however, humans are considered to be relatively more sensitive to such changes than rats, and the potential for reproductive toxicity in humans from low concentrations of cyanide warrants further investigation. NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.