Revisiting the testicular toxicity of cyanide: Assessment of the new and existing literature

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Background Based on new testing, we re‐assess U.S. EPA and California OEHHA conclusions regarding male reproductive toxicity associated with cyanide exposure. Methods Literature identified by ATSDR, ECETOC and EPA was complemented by studies conducted after 2006. Relevant studies were scored for quality using ToxRTool. Results Eleven pertinent animal investigations were identified; five with quality scores of 1 were evaluated in‐depth. The NTP 13‐week drinking water study of NaCN in rats reported significantly decreased water intakes and reduced cauda epididymal weights; altered sperm parameters occurred in high‐dose rats. When compared to contemporaneous historical control data (HCD), the mean cauda epididymal weights of cyanide‐treated rats in the NTP study were within HCD, whereas control weights exceeded HCD. A new 13‐week drinking water study used the same design with additional features (individually caged rats, “paired water” controls, thyroid hormone determinations, post‐treatment recovery) and found a smaller decrease in water consumption (11% versus 18% at 300 ppm) and no treatment‐related changes in male reproductive measures. Although thyroid/parathyroid weights were increased at 300 ppm, histopathology and thyroid hormone levels were unaffected. The remaining high‐quality cyanide studies reported no adverse findings in male reproductive organs. Unconfounded sperm measures were not adversely affected in any quality 1 studies. Conclusions Changes in the male reproductive system reported after cyanide exposure in the NTP study were not reproducible, unlikely to be treatment‐related, and should not be used as the sole basis for human health assessments.